Gene Summary

Gene:CNTRL; centriolin
Aliases: FAN, CEP1, CEP110, bA165P4.1
Summary:This gene encodes a centrosomal protein required for the centrosome to function as a microtubule organizing center. The gene product is also associated with centrosome maturation. One version of stem cell myeloproliferative disorder is the result of a reciprocal translocation between chromosomes 8 and 9, with the breakpoint associated with fibroblast growth factor receptor 1 and centrosomal protein 1. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 31 August, 2019

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: CNTRL (cancer-related)

Atiya HI, Dvorkin-Gheva A, Hassell J, et al.
Intraductal Adaptation of the 4T1 Mouse Model of Breast Cancer Reveals Effects of the Epithelial Microenvironment on Tumor Progression and Metastasis.
Anticancer Res. 2019; 39(5):2277-2287 [PubMed] Related Publications
BACKGROUND: Low success rates in oncology drug development are prompting re-evaluation of preclinical models, including orthotopic tumor engraftment. In breast cancer models, tumor cells are typically injected into mouse mammary fat pads (MFP). However, this approach bypasses the epithelial microenvironment, potentially altering tumor properties in ways that affect translational application.
MATERIALS AND METHODS: Tumors were generated by mammary intraductal (MIND) engraftment of 4T1 carcinoma cells. Growth, histopathology, and molecular features were quantified.
RESULTS: Despite growth similar to that of 4T1 MFP tumors, 4T1 MIND tumors exhibit distinct histopathology and increased metastasis. Furthermore, >6,000 transcripts were found to be uniquely up-regulated in 4T1 MIND tumor cells, including genes that drive several cancer hallmarks, in addition to two known therapeutic targets that were not up-regulated in 4T1 MFP tumor cells.
CONCLUSION: Engraftment into the epithelial microenvironment generates tumors that more closely recapitulate the complexity of malignancy, suggesting that intraductal adaptation of orthotopic mammary models may be an important step towards improving outcomes in preclinical drug screening and development.

Liu B, Zhang Y, Fan Y, et al.
Leucine-rich repeat neuronal protein-1 suppresses apoptosis of gastric cancer cells through regulation of Fas/FasL.
Cancer Sci. 2019; 110(7):2145-2155 [PubMed] Free Access to Full Article Related Publications
Gastric cancer (GC) is a common cause of cancer-related death worldwide. As a result of the lack of reliable diagnostic or prognostic biomarkers for GC, patient prognosis is still poor. Therefore, there is an urgent need for studies examining the underlying pathogenesis of GC in order to find effective biomarkers. LRRN1 (leucine-rich repeat neuronal protein-1) is a type I transmembrane protein that plays an important role in the process of nerve development and regeneration. However, its role in cancer, especially in GC, remains unclear. In the present study, we found that LRRN1 expression is upregulated in GC tissues and that high LRRN1 expression is associated with poor prognosis. siRNA and shRNA-mediated knockdowns of LRRN1 expression promoted GC cell apoptosis and activation of the Fas/FasL pathway. LRRN1 knockdown also resulted in upregulation of JUN, a subunit of the transcription factor AP-1 (activator protein-1). This suggests that LRRN1 suppresses GC cell apoptosis by downregulating AP-1, resulting in inhibition of the Fas/FasL pathway. These results confirm that LRRN1 plays a significant role in GC pathogenesis. Moreover, LRRN1 may be a potential prognostic biomarker and therapeutic target for GC.

Gao Y, Li L, Li T, et al.
Simvastatin delays castration‑resistant prostate cancer metastasis and androgen receptor antagonist resistance by regulating the expression of caveolin‑1.
Int J Oncol. 2019; 54(6):2054-2068 [PubMed] Free Access to Full Article Related Publications
The failure of androgen deprivation therapy in prostate cancer treatment mainly results from drug resistance to androgen receptor antagonists. Although an aberrant caveolin‑1 (Cav‑1) expression has been reported in multiple tumor cell lines, it is unknown whether it is responsible for the progression of castration‑resistant prostate cancer (CRPC). Thus, the aim of the present study was to determine whether Cav‑1 can be used as a key molecule for the prevention and treatment of CRPC, and to explore its mechanism of action in CRPC. For this purpose, tissue and serum samples from patients with primary prostate cancer and CRPC were analyzed using immunohistochemistry and enzyme‑linked immunosorbent assay, which revealed that Cav‑1 was overexpressed in CRPC. Furthermore, Kaplan‑Meier survival analysis and univariate Cox proportional hazards regression analysis demonstrated that Cav‑1 expression in tumors was an independent risk factor for the occurrence of CRPC and was associated with a shorter recurrence‑free survival time in patients with CRPC. Receiver operating characteristic curves suggested that serum Cav‑1 could be used as a diagnostic biomarker for CRPC (area under the curve, 0.876) using a cut‑off value of 0.68 ng/ml (with a sensitivity of 82.1% and specificity of 80%). In addition, it was determined that Cav‑1 induced the invasion and migration of CRPC cells by the activation of the H‑Ras/phosphoinositide‑specific phospholipase Cε signaling cascade in the cell membrane caveolae. Importantly, simvastatin was able to augment the anticancer effects of androgen receptor antagonists by downregulating the expression of Cav‑1. Collectively, the findings of this study provide evidence that Cav‑1 is a promising predictive biomarker for CRPC and that lowering cholesterol levels with simvastatin or interfering with the expression of Cav‑1 may prove to be a useful strategy with which to prevent and/or treat CRPC.

Fan X, Wang Y, Tang XQ
Extracting predictors for lung adenocarcinoma based on Granger causality test and stepwise character selection.
BMC Bioinformatics. 2019; 20(Suppl 7):197 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Lung adenocarcinoma is the most common type of lung cancer, with high mortality worldwide. Its occurrence and development were thoroughly studied by high-throughput expression microarray, which produced abundant data on gene expression, DNA methylation, and miRNA quantification. However, the hub genes, which can be served as bio-markers for discriminating cancer and healthy individuals, are not well screened.
RESULT: Here we present a new method for extracting gene predictors, aiming to obtain the least predictors without losing the efficiency. We firstly analyzed three different expression microarrays and constructed multi-interaction network, since the individual expression dataset is not enough for describing biological behaviors dynamically and systematically. Then, we transformed the undirected interaction network to directed network by employing Granger causality test, followed by the predictors screened with the use of the stepwise character selection algorithm. Six predictors, including TOP2A, GRK5, SIRT7, MCM7, EGFR, and COL1A2, were ultimately identified. All the predictors are the cancer-related, and the number is very small fascinating diagnosis. Finally, the validation of this approach was verified by robustness analyses applied to six independent datasets; the precision is up to 95.3% ∼ 100%.
CONCLUSION: Although there are complicated differences between cancer and normal cells in gene functions, cancer cells could be differentiated in case that a group of special genes expresses abnormally. Here we presented a new, robust, and effective method for extracting gene predictors. We identified as low as 6 genes which can be taken as predictors for diagnosing lung adenocarcinoma.

Yang X, Miao BS, Wei CY, et al.
Lymphoid-specific helicase promotes the growth and invasion of hepatocellular carcinoma by transcriptional regulation of centromere protein F expression.
Cancer Sci. 2019; 110(7):2133-2144 [PubMed] Free Access to Full Article Related Publications
Lymphoid-specific helicase (LSH) is overexpressed in tumor tissues and its overexpression is associated with poor prognosis in several cancers. However, the role and molecular mechanism of LSH in hepatocellular carcinoma (HCC) remains largely unknown. Herein, we report that LSH was overexpressed in tumor tissues of HCC, and overexpression of LSH was associated with poor prognosis from a public HCC database, and validated by clinical samples from our department. Ectopic LSH expression promoted the growth of HCC cells in vivo and in vitro. Mechanistically, LSH overexpression promoted tumor growth by activating transcription of centromere protein F (CENPF). Clinically, overexpression of LSH and/or CENPF correlated with shorter overall survival and higher cumulative recurrence rates of HCC. In conclusion, LSH promotes tumor growth of HCC through transcriptional regulation of CENPF expression. Therefore, LSH may be a novel predictor for prognosis and a potential therapeutic target for HCC.

Xing R, Zhou Y, Yu J, et al.
Whole-genome sequencing reveals novel tandem-duplication hotspots and a prognostic mutational signature in gastric cancer.
Nat Commun. 2019; 10(1):2037 [PubMed] Free Access to Full Article Related Publications
Genome-wide analysis of genomic signatures might reveal novel mechanisms for gastric cancer (GC) tumorigenesis. Here, we analysis structural variations (SVs) and mutational signatures via whole-genome sequencing of 168 GCs. Our data demonstrates diverse models of complex SVs operative in GC, which lead to high-level amplification of oncogenes. We find varying proportion of tandem-duplications (TDs) among individuals and identify 24 TD hotspots involving well-established cancer genes such as CCND1, ERBB2 and MYC. Specifically, we nominate a novel hotspot involving the super-enhancer of ZFP36L2 presents in approximately 10% GCs from different cohorts, the oncogenic role of which is further confirmed by experimental data. In addition, our data reveal a mutational signature, specifically occurring in noncoding region, significantly enriched in tumors with cadherin 1 mutations, and associated with poor prognoses. Collectively, our data suggest that TDs might serve as an important mechanism for cancer gene activation and provide a novel signature for stratification.

Fan CM, Wang JP, Tang YY, et al.
circMAN1A2 could serve as a novel serum biomarker for malignant tumors.
Cancer Sci. 2019; 110(7):2180-2188 [PubMed] Free Access to Full Article Related Publications
Novel diagnostic and prognostic biomarkers of cancers are needed to improve precision medicine. Circular RNAs act as important regulators in cancers at the transcriptional and posttranscriptional levels. The circular RNA circMAN1A2 is highly expressed in nasopharyngeal carcinoma according to our previous RNA sequencing data; however, the expression and functions of circMAN1A2 in cancers are still obscure. Therefore, in this study, we evaluated the expression of circMAN1A2 in the sera of patients with nasopharyngeal carcinoma and other malignant tumors and analyzed its correlations with clinical features and diagnostic values. The expression levels of circMAN1A2 were detected by quantitative real-time PCR, and the correlations of clinical features with circMAN1A2 expression were analyzed by χ

Song W, Gu Y, Lu S, et al.
LncRNA TRERNA1 facilitates hepatocellular carcinoma metastasis by dimethylating H3K9 in the CDH1 promoter region via the recruitment of the EHMT2/SNAI1 complex.
Cell Prolif. 2019; 52(4):e12621 [PubMed] Related Publications
OBJECTIVES: Long non-coding RNAs (LncRNAs) play an important role in hepatocellular carcinoma development, however, as a crucial driver of hepatocellular carcinoma (HCC) metastasis, their functions in tumour metastasis remain largely unknown.
MATERIALS AND METHODS: The lncRNA TRERNA1 expression levels were detected in HCC by quantitative real-time PCR (qPCR). The function of TRERNA1 was examined by wound-healing assays, transwell assays and tail vein injection experiments. The potential regulatory mechanisms of TRERNA1 on its target genes were explored by ChIP, RIP, IP and WB assays.
RESULTS: Elevated TRERNA1 levels promoted HCC cell migration and invasion in vitro and in vivo. TRERNA1 recruited EHMT2 to dimethylate H3K9 in the CDH1 promoter region. Furthermore, EHMT2 bound to SNAI1 to suppress CDH1 expression in HCC cells. After inhibiting TRERNA1, the expression level of CDH1 was restored and was involved in the regulation of the EHMT2/SNAI1 complex. The level of TRERNA1 was positively correlated with tumour metastasis and was negatively correlated with the expression of CDH1 in HCC tissues.
CONCLUSIONS: For the first time, the current study reveals that TRERNA1 promotes cell metastasis and the invasion of HCC via the recruitment of EHMT2 and/or the EHMT2/SNAI1 complex to suppress CDH1. These data identify a novel mechanism that regulates TRERNA1 in metastatic HCC and provides a potential targeted therapy for HCC patients.

Mao W, Huang X, Wang L, et al.
Circular RNA hsa_circ_0068871 regulates FGFR3 expression and activates STAT3 by targeting miR-181a-5p to promote bladder cancer progression.
J Exp Clin Cancer Res. 2019; 38(1):169 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: FGFR3 plays an important role in the development of bladder cancer (BCa). Hsa_circ_0068871 is a circRNA generated from several exons of FGFR3. However, the potential functional role of hsa_circ_0068871 in BCa remains largely unknown. Here we aim to evaluate the role of hsa_circ_0068871 in BCa.
METHODS: We selected miR-181a-5p as the potential target miRNA of hsa_circ_0068871. The expression levels of hsa_circ_0068871 and miR-181a-5p were examined in BCa tissues and paired adjacent normal tissues by quantitative real-time PCR. To characterize the function of hsa_circ_0068871, BCa cell lines were stably infected with lentivirus targeting hsa_circ_0068871, followed by examinations of cell proliferation, migration and apoptosis. In addition, xenografts experiment in nude mice were performed to evaluate the effect of hsa_circ_0068871 in BCa. Biotinylated RNA probe pull-down assay, fluorescence in situ hybridization and luciferase reporter assay were conducted to confirm the relationship between hsa_circ_0068871, miR-181a-5p and FGFR3.
RESULTS: Hsa_circ_0068871 is over-expressed in BCa tissues and cell lines, whereas miR-181a-5p expression is repressed. Depletion of has_circ_0068871 or upregulation of miR-181a-5p inhibited the proliferation and migration of BCa cells in vitro and in vivo. Mechanistically, hsa_circ_0068871 upregulated FGFR3 expression and activated STAT3 by targeting miR-181a-5p to promote BCa progression.
CONCLUSIONS: Hsa_circ_0068871 regulates the miR-181a-5p/FGFR3 axis and activates STAT3 to promote BCa progression, and it may serve as a potential biomarker.

Chen J, Chen J, He F, et al.
Design of a Targeted Sequencing Assay to Detect Rare Mutations in Circulating Tumor DNA.
Genet Test Mol Biomarkers. 2019; 23(4):264-269 [PubMed] Related Publications
BACKGROUND: Qualitative and quantitative detection of circulating tumor DNA (ctDNA) is a liquid biopsy technology used for early cancer diagnosis. However, the plasma ctDNA content is extremely low, so it is difficult to detect somatic mutations of tumors using conventional sequencing methods. Target region sequencing (TRS) technology, through enrichment of the target genomic region followed by next generation sequencing, overcomes this challenge and has been widely used in ctDNA sequencing.
METHODS: We designed a ctDNA sequencing panel to capture 128 tumor genes, and tested the performance of the panel by running TRS for ctDNA of a clear cell renal cell carcinoma (ccRCC) patient and 12 breast cancer patients.
RESULTS: TRS using the new ctDNA panel at more than 500 × coverage depth achieved almost the same accuracy as traditional whole-exome sequencing (WES). PBRM1 p.L641V was detected in the plasma sample of the ccRCC patient with an allele frequency of 0.2%. The ctDNA of 12 breast cancer patients was sequenced at a depth of 500-fold, achieving 99.89% coverage; 34 genes were detected with mutations, including the drug target genes BRCA2, PTEN, TP53, APC, KDR, and NOTCH2.
CONCLUSIONS: This TRS new ctDNA panel can be used to detect mutations in cell-free DNA from multiple types of cancer.

Ai L, Mu S, Sun C, et al.
Myeloid-derived suppressor cells endow stem-like qualities to multiple myeloma cells by inducing piRNA-823 expression and DNMT3B activation.
Mol Cancer. 2019; 18(1):88 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Myeloid-derived suppressor cells (MDSCs) and cancer stem cells (CSCs) are two important cellular components in the tumor microenvironment, which may modify the cancer phenotype and affect patient survival. However, the crosstalk between MDSCs and multiple myeloma stem cells (MMSCs) are relatively poorly understood.
METHODS: The frequencies of granulocytic-MDSCs (G-MDSCs) in MM patients were detected by flow cytometry and their association with the disease stage and patient survival were analyzed. RT-PCR, flow cytometry, western blot and sphere formation assays were performed to investigate the effects of G-MDSCs, piRNA-823 and DNA methylation on the maintenance of stemness in MM. Then a subcutaneous tumor mouse model was constructed to analyze tumor growth and angiogenesis after G-MDSCs induction and/or piRNA-823 knockdown in MM cells.
RESULTS: Our clinical dataset validated the association between high G-MDSCs levels and poor overall survival in MM patients. In addition, for the first time we showed that G-MDSCs enhanced the side population, sphere formation and expression of CSCs core genes in MM cells. Moreover, the mechanism study showed that G-MDSCs triggered piRNA-823 expression, which then promoted DNA methylation and increased the tumorigenic potential of MM cells. Furthermore, silencing of piRNA-823 in MM cells reduced the stemness of MMSCs maintained by G-MDSCs, resulting in decreased tumor burden and angiogenesis in vivo.
CONCLUSION: Altogether, these data established a cellular, molecular, and clinical network among G-MDSCs, piRNA-823, DNA methylation and CSCs core genes, suggesting a new anti-cancer strategy targeting both G-MDSCs and CSCs in MM microenvironment.

Gao L, Hu Y, Tian Y, et al.
Lung cancer deficient in the tumor suppressor GATA4 is sensitive to TGFBR1 inhibition.
Nat Commun. 2019; 10(1):1665 [PubMed] Free Access to Full Article Related Publications
Lung cancer is the leading cause of cancer-related deaths worldwide. Tumor suppressor genes remain to be systemically identified for lung cancer. Through the genome-wide screening of tumor-suppressive transcription factors, we demonstrate here that GATA4 functions as an essential tumor suppressor in lung cancer in vitro and in vivo. Ectopic GATA4 expression results in lung cancer cell senescence. Mechanistically, GATA4 upregulates multiple miRNAs targeting TGFB2 mRNA and causes ensuing WNT7B downregulation and eventually triggers cell senescence. Decreased GATA4 level in clinical specimens negatively correlates with WNT7B or TGF-β2 level and is significantly associated with poor prognosis. TGFBR1 inhibitors show synergy with existing therapeutics in treating GATA4-deficient lung cancers in genetically engineered mouse model as well as patient-derived xenograft (PDX) mouse models. Collectively, our work demonstrates that GATA4 functions as a tumor suppressor in lung cancer and targeting the TGF-β signaling provides a potential way for the treatment of GATA4-deficient lung cancer.

Mok TSK, Wu YL, Kudaba I, et al.
Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.
Lancet. 2019; 393(10183):1819-1830 [PubMed] Related Publications
BACKGROUND: First-line pembrolizumab monotherapy improves overall and progression-free survival in patients with untreated metastatic non-small-cell lung cancer with a programmed death ligand 1 (PD-L1) tumour proportion score (TPS) of 50% or greater. We investigated overall survival after treatment with pembrolizumab monotherapy in patients with a PD-L1 TPS of 1% or greater.
METHODS: This randomised, open-label, phase 3 study was done in 213 medical centres in 32 countries. Eligible patients were adults (≥18 years) with previously untreated locally advanced or metastatic non-small-cell lung cancer without a sensitising EGFR mutation or ALK translocation and with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, life expectancy 3 months or longer, and a PD-L1 TPS of 1% or greater. Randomisation was computer generated, accessed via an interactive voice-response and integrated web-response system, and stratified by region of enrolment (east Asia vs rest of world), ECOG performance status score (0 vs 1), histology (squamous vs non-squamous), and PD-L1 TPS (≥50% vs 1-49%). Enrolled patients were randomly assigned 1:1 in blocks of four per stratum to receive pembrolizumab 200 mg every 3 weeks for up to 35 cycles or the investigator's choice of platinum-based chemotherapy for four to six cycles. Primary endpoints were overall survival in patients with a TPS of 50% or greater, 20% or greater, and 1% or greater (one-sided significance thresholds, p=0·0122, p=0·0120, and p=0·0124, respectively) in the intention-to-treat population, assessed sequentially if the previous findings were significant. This study is registered at, number NCT02220894.
FINDINGS: From Dec 19, 2014, to March 6, 2017, 1274 patients (902 men, 372 women, median age 63 years [IQR 57-69]) with a PD-L1 TPS of 1% or greater were allocated to pembrolizumab (n=637) or chemotherapy (n=637) and included in the intention-to-treat population. 599 (47%) had a TPS of 50% or greater and 818 patients (64%) had a TPS of 20% or greater. As of Feb 26, 2018, median follow-up was 12·8 months. Overall survival was significantly longer in the pembrolizumab group than in the chemotherapy group in all three TPS populations (≥50% hazard ratio 0·69, 95% CI 0·56-0·85, p=0·0003; ≥20% 0·77, 0·64-0·92, p=0·0020, and ≥1% 0·81, 0·71-0·93, p=0·0018). The median surival values by TPS population were 20·0 months (95% CI 15·4-24·9) for pembrolizumab versus 12·2 months (10·4-14·2) for chemotherapy, 17·7 months (15·3-22·1) versus 13·0 months (11·6-15·3), and 16·7 months (13·9-19·7) versus 12·1 months (11·3-13·3), respectively. Treatment-related adverse events of grade 3 or worse occurred in 113 (18%) of 636 treated patients in the pembrolizumab group and in 252 (41%) of 615 in the chemotherapy group and led to death in 13 (2%) and 14 (2%) patients, respectively.
INTERPRETATION: The benefit-to-risk profile suggests that pembrolizumab monotherapy can be extended as first-line therapy to patients with locally advanced or metastatic non-small-cell lung cancer without sensitising EGFR or ALK alterations and with low PD-L1 TPS.
FUNDING: Merck Sharp & Dohme.

Yang L, Peng X, Li Y, et al.
Long non-coding RNA HOTAIR promotes exosome secretion by regulating RAB35 and SNAP23 in hepatocellular carcinoma.
Mol Cancer. 2019; 18(1):78 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Emerging evidence indicates that tumor cells release a large amount of exosomes loaded with cargos during tumorigenesis. Exosome secretion is a multi-step process regulated by certain related molecules. Long non-coding RNAs (lncRNAs) play an important role in hepatocellular carcinoma (HCC) progression. However, the role of lncRNA HOTAIR in regulating exosome secretion in HCC cells remains unclear.
METHODS: We analyzed the relationship between HOTAIR expression and exosome secretion-related genes using gene set enrichment analysis (GSEA). Nanoparticle tracking analysis was performed to validate the effect of HOTAIR on exosome secretion. The transport of multivesicular bodies (MVBs) after overexpression of HOTAIR was detected by transmission electron microscopy and confocal microscopy analysis of cluster determinant 63 (CD63) with synaptosome associated protein 23 (SNAP23). The mechanism of HOTAIR's regulation of Ras-related protein Rab-35 (RAB35), vesicle associated membrane protein 3 (VAMP3), and SNAP23 was assessed using confocal co-localization analysis, phosphorylation assays, and rescue experiments.
RESULTS: We found an enrichment of exosome secretion-related genes in the HOTAIR high expression group. HOTAIR promoted the release of exosomes by inducing MVB transport to the plasma membrane. HOTAIR regulated RAB35 expression and localization, which controlled the docking process. Moreover, HOTAIR facilitated the final step of fusion by influencing VAMP3 and SNAP23 colocalization. In addition, we validated that HOTAIR induced the phosphorylation of SNAP23 via mammalian target of rapamycin (mTOR) signaling.
CONCLUSION: Our study demonstrated a novel function of lncRNA HOTAIR in promoting exosome secretion from HCC cells and provided a new understanding of lncRNAs in tumor cell biology.

Cowman S, Fan YN, Pizer B, Sée V
Decrease of Nibrin expression in chronic hypoxia is associated with hypoxia-induced chemoresistance in some brain tumour cells.
BMC Cancer. 2019; 19(1):300 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Solid tumours are less oxygenated than normal tissues. This is called tumour hypoxia and leads to resistance to radiotherapy and chemotherapy. The molecular mechanisms underlying such resistance have been investigated in a range of tumour types, including the adult brain tumours glioblastoma, yet little is known for paediatric brain tumours. Medulloblastoma (MB) is the most common malignant brain tumour in children. We aimed to elucidate the impact of hypoxia on the sensitivity of MB cells to chemo- and radiotherapy.
METHODS: We used two MB cell line (D283-MED and MEB-Med8A) and a widely used glioblastoma cell line (U87MG) for comparison. We applied a range of molecular and cellular techniques to measure cell survival, cell cycle progression, protein expression and DNA damage combined with a transcriptomic micro-array approach in D283-MED cells, for global gene expression analysis in acute and chronic hypoxic conditions.
RESULTS: In D283-MED and U87MG, chronic hypoxia (5 days), but not acute hypoxia (24 h) induced resistance to chemotherapy and X-ray irradiation. This acquired resistance upon chronic hypoxia was present but less pronounced in MEB-Med8A cells. Using transcriptomic analysis in D283-MED cells, we found a large transcriptional remodelling upon long term hypoxia, in particular the expression of a number of genes involved in detection and repair of double strand breaks (DSB) was altered. The levels of Nibrin (NBN) and MRE11, members of the MRN complex (MRE11/Rad50/NBN) responsible for DSB recognition, were significantly down-regulated. This was associated with a reduction of Ataxia Telangiectasia Mutated (ATM) activation by etoposide, indicating a profound dampening of the DNA damage signalling in hypoxic conditions. As a consequence, p53 activation by etoposide was reduced, and cell survival enhanced. Whilst U87MG shared the same dampened p53 activity, upon chemotherapeutic drug treatment in chronic hypoxic conditions, these cells used a different mechanism, independent of the DNA damage pathway.
CONCLUSION: Together our results demonstrate a new mechanism explaining hypoxia-induced resistance involving the alteration of the response to DSB in D283-MED cells, but also highlight the cell type to cell type diversity and the necessity to take into account the differing tumour genetic make-up when considering re-sensitisation therapeutic protocols.

Fan C, Liu N
Identification of dysregulated microRNAs associated with diagnosis and prognosis in triple‑negative breast cancer: An in silico study.
Oncol Rep. 2019; 41(6):3313-3324 [PubMed] Related Publications
Triple‑negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with limited treatment options combined with poor rates of survival. Given the lack of appropriate prognostic biomarkers for TNBC patients, the present study aimed to identify potential dysregulated miRNAs capable of providing a diagnosis and predicting overall survival for TNBC patients. A total of 289 miRNAs were aberrantly regulated in TNBC tissue compared to adjacent, non‑cancerous tissues and 96 microRNAs (miRNAs) in TNBC compared with non‑triple‑negative breast cancer (nTNBC) samples. Receiver operating characteristic (ROC) curve analysis suggested that 4 miRNAs (hsa‑miR‑10a, hsa‑miR‑18a, hsa‑miR‑135b and hsa‑miR‑577) had diagnostic value [area under curve (AUC) >0.8]. A 4‑miRNA signature consisting of hsa‑miR‑148b, hsa‑miR‑203a, hsa‑miR‑203b and hsa‑miR‑3922 was constructed for prediction of prognosis. A multivariate Cox's proportional hazards regression model indicated that the 4‑miRNA signature was an independent prognostic factor of other clinical variables in patients with TNBC. Functional analysis of the target genes of the miRNA signature demonstrated that the prolactin signaling pathway and miRNAs in cancer were significantly enriched. In conclusion, the results in the present study may highlight efficient biomarkers for the diagnosis of TNBC and its prognosis. In‑depth exploitation of these miRNAs will help define and develop novel molecular therapeutic strategies and improve prognosis for TNBC patients.

Fan X, Wu X
MicroRNA-122-5p promotes the development of non-small cell lung cancer via downregulating p53 and activating PI3K-AKT pathway.
J BUON. 2019 Jan-Feb; 24(1):273-279 [PubMed] Related Publications
PURPOSE: To investigate the role of microRNA-122-5p in the pathogenesis of non-small cell lung cancer (NSCLC) and its underlying mechanism.
METHODS: A total of 72 pairs of NSCLC tissues and paracancerous tissues were collected. The expression level of microRNA-122-5p in NSCLC tissues and paracancerous tissues were detected by qRT-PCR (quantitative real-time polymerase chain reaction). The relationship between microRNA-122-5p expression and the clinical prognosis of NSCLC patients was then analyzed. Bioinformatics prediction and luciferase activity assay were performed to validate the direct binding of microRNA-122-5p and p53. Cell cycle, proliferation, and apoptosis were detected after microRNA-122-5p knockdown in NSCLC cells. The regulatory effect of microRNA-122-5p on promoting NSCLC development was detected by Western blot.
RESULTS: MicroRNA-122-5p was more overexpressed in NSCLC tissues than in paracancerous tissues. MicroRNA-122-5p expression was negatively correlated with survival rate of NSCLC patients. Besides, microRNA-122-5p knockdown remarkably inhibited the proliferation and cell cycle advancement and increased apoptosis of NSCLC cells. Luciferase reporter gene assay and Western blot results indicated that microRNA-122-5p downregulated p53 and activated PI3K-AKT pathway, thereby promoting NSCLC development.
CONCLUSION: MicroRNA-122-5p is overexpressed in NSCLC. Overexpression of microRNA-122-5p promotes NSCLC development by downregulating p53 and activating PI3K-AKT pathway.

Wu Y, Xie Z, Chen J, et al.
Circular RNA circTADA2A promotes osteosarcoma progression and metastasis by sponging miR-203a-3p and regulating CREB3 expression.
Mol Cancer. 2019; 18(1):73 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: As a subclass of noncoding RNAs, circular RNAs (circRNAs) have been demonstrated to play a critical role in regulating gene expression in eukaryotes. Recent studies have revealed the pivotal functions of circRNAs in cancer progression. However, little is known about the role of circTADA2A, also named hsa_circ_0043278, in osteosarcoma (OS).
METHODS: CircTADA2A was selected from a previously reported circRNA microarray comparing OS cell lines and normal bone cells. QRT-PCR was used to detect the expression of circTADA2A in OS tissue and cell lines. Luciferase reporter, RNA immunoprecipitation (RIP), RNA pull-down and fluorescence in situ hybridization (FISH) assays were performed to confirm the binding of circTADA2A with miR-203a-3p. OS cells were stably transfected with lentiviruses, and Transwell migration, Matrigel invasion, colony formation, proliferation, apoptosis, Western blotting, and in vivo tumorigenesis and metastasis assays were employed to evaluate the roles of circTADA2A, miR-203a-3p and CREB3.
RESULTS: Our findings demonstrated that circTADA2A was highly expressed in both OS tissue and cell lines, and circTADA2A inhibition attenuated the migration, invasion and proliferation of OS cells in vitro as well as tumorigenesis and metastasis in vivo. A mechanistic study revealed that circTADA2A could readily sponge miR-203a-3p to upregulate the expression of CREB3, which was identified as a driver gene in OS. Furthermore, miR-203a-3p inhibition or CREB3 overexpression could reverse the circTADA2A silencing-induced impairment of malignant tumor behavior.
CONCLUSIONS: CircTADA2A functions as a tumor promoter in OS to increase malignant tumor behavior through the miR-203a-3p/CREB3 axis, which could be a novel target for OS therapy.

Li F, Fan X, Wang X, et al.
Genetic association and interaction of PD1 and TIM3 polymorphisms in susceptibility of chronic hepatitis B virus infection and hepatocarcinogenesis.
Discov Med. 2019; 27(147):79-92 [PubMed] Related Publications
The PD1 (rs2227982, rs41386349, rs6710479, rs7421861, and rs7565639) and TIM3 (rs11134551, rs11742259, rs246871, rs25855, and rs31223) polymorphisms were examined in 362 patients with chronic hepatitis B virus (HBV) infection, 91 HBV infection resolvers, and 158 healthy controls. Univariate logistic regression was carried out by SNPstats to detect the associations. Multifactor dimensionality reduction (MDR) analysis was performed to explore interactions between PD1 and TIM3 polymorphisms. Associations of polymorphisms with clinical disease were also evaluated. Compared with patients with chronic HBV infection and healthy controls, HBV infection resolvers had a lower frequency of PD1 rs41386349 allele A, higher frequency of PD1 rs6710479 allele C, and higher frequency of TIM3 rs246871 genotypes TC and TC + CC. A best MDR model composed of PD1 rs2227982, rs41386349, and rs7421861, and TIM3 rs11134551, rs11742259, rs246871, rs25855, and rs31223 was observed between patients with chronic HBV infection and HBV infection resolvers (maximum testing balance accuracy, 0.5803; maximum cross-validation consistency, 9/10; P = 0.0010). PD1 rs2227982, rs6710479, and rs7421861 were associated with a higher hepatocellular carcinoma risk. These findings suggest that PD1 rs41386349 and rs6710479 and TIM3 rs246871 and interactions between PD1 and TIM3 polymorphisms may affect the susceptibility of chronic HBV infection and PD1 rs2227982, rs6710479, and rs7421861 may implicate in hepatocarcinogenesis.

Fang C, Jiang B, Shi X, Fan C
Hes3 Enhances the Malignant Phenotype of Lung Cancer through Upregulating Cyclin D1, Cyclin D3 and MMP7 Expression.
Int J Med Sci. 2019; 16(3):470-476 [PubMed] Free Access to Full Article Related Publications

Li N, Fan X, Wang X, et al.
Autophagy-Related 5 Gene rs510432 Polymorphism Is Associated with Hepatocellular Carcinoma in Patients with Chronic Hepatitis B Virus Infection.
Immunol Invest. 2019; 48(4):378-391 [PubMed] Related Publications
BACKGROUND: Despite the identification of autophagy-related protein 5 (ATG5) as a molecule involved in the activated autophagy machinery during hepatitis B virus (HBV) infection and hepatocarcinogenesis, the consequences of ATG5 mutation carriage for patients with chronic HBV infection remain unclear. This study examined the association of ATG5 polymorphisms with HBV-related diseases including hepatocellular carcinoma (HCC).
PATIENTS AND METHODS: Two functionally relevant polymorphisms ATG5 rs573775 and rs510432 were genotyped by ligase detection reaction-polymerase chain reaction in 403 patients with chronic HBV infection (171 chronic hepatitis, 119 cirrhosis and 113 HCC) and 196 healthy controls. Univariate and multivariate logistic regression was performed to evaluate factors associated with HCC.
RESULTS: The rs573775 genotype and allele frequencies had no significant differences between patients with different clinical diseases. However, HCC patients had significantly higher frequency of rs510432 genotype AA (odds ratio [OR] 2.185, 95% confidence interval [CI] 1.042-4.581, P = 0.037, P value by Bonferroni correction [P
CONCLUSION: These results indicate that rs510432 genotypes AA+GA are associated with disease progression and HCC risk in chronic HBV infection, providing novel evidence for a role of ATG5 in the pathogenesis of HBV-related HCC.
ABBREVIATIONS: HBV: hepatitis B virus; HCC hepatocellular carcinoma; TNFSF10: tumor necrosis factor superfamily member 10; ATG5: autophagy-related protein 5; DNA: deoxyribonucleic acid; LDR-PCR: ligase detection reactions-polymerase chain reaction; PCR: polymerase chain reaction; SLE: systemic lupus erythematosus; BD: Behçet's disease; IL-10: interlukin-10; LPS: lipopolysaccharide; PBMC: peripheral blood mononuclear cells; CWP: coal workers' pneumoconiosis; TNF-α: tumor necrosis factor-α.

Zhang Z, Zhang W, Mao J, et al.
miR-186-5p Functions as a Tumor Suppressor in Human Osteosarcoma by Targeting FOXK1.
Cell Physiol Biochem. 2019; 52(3):553-564 [PubMed] Related Publications
BACKGROUND/AIMS: Aberrantly expressed miRNAs play a vital role in the development of some cancers, such as human osteosarcoma (OS). However, the detailed molecular mechanisms underlying miR-186-5p-involved osteosarcoma are unclear.
METHODS: qRT-PCR and western blot analysis were employed to measure the expressions of miR-186-5p and forkhead box k1 (FOXK1). CCK-8 assay evaluated the effect of miR-186-5p and FOXK1 on cell proliferation. Transwell assay confirmed cell migration and invasion. Eventually, the dual-luciferase reporter assay validated 3'-untranslated region (3'-UTR) of FOXK1 as a direct target of miR-186-5p.
RESULTS: Down-regulation of miR-186-5p was identified in OS tissues and cell lines, and negatively correlated with distant metastasis, Enneking stage and poor 5-year prognosis as well as the expression of forkhead box k1 (FOXK1) protein. Further assays demonstrated that miR-186-5p overexpression had inhibitory effects on in-vitro cell proliferation, cell cycle, and in-vivo tumor growth. miR-186-5p overexpression also inhibited the epithelial-tomesenchymal transition (EMT), migration and invasion of OS cells. Importantly, miR-186-5p directly targeted FOXK1 3'-UTR and negatively regulated its expression. Silencing of FOXK1 expression enhanced the inhibitory effects of miR-186-5p on OS cell proliferation, migration and invasion.
CONCLUSION: These findings highlighted miR-186-5p as a tumor suppressor in the regulation of progression and metastatic potential of OS, and may benefit the development of therapies targeting miR-186-5p in patients with OS.

Tang Y, Ren F, Cong X, et al.
Overexpression of ribonuclease inhibitor induces autophagy in human colorectal cancer cells via the Akt/mTOR/ULK1 pathway.
Mol Med Rep. 2019; 19(5):3519-3526 [PubMed] Free Access to Full Article Related Publications
Ribonuclease inhibitor (RI), also termed angiogenin inhibitor, acts as the inhibitor of ribonucleolytic activity of RNase A and angiogenin. The expression of RI has been investigated in melanoma and bladder cancer cells. However, the precise role of RI in tumorigenesis, in addition to RI‑induced autophagy, remains poorly understood. In the present study, it was demonstrated that RI positively regulated autophagy in human colorectal cancer (CRC) cells as indicated by an increase in light chain 3 (LC3)‑II levels. Furthermore, RI regulated cell survival in HT29 cells. In addition, autophagy‑associated proteins, including beclin‑1 and autophagy‑related protein 13, were increased in response to RI‑induced autophagy, and the protein kinase B (Akt)/mechanistic target of rapamycin (mTOR)/Unc‑51 like autophagy activating kinase (ULK1) pathway may be involved in the activation of autophagy induced by RI overexpression. Taken together, the evidence of the present study indicated that the overexpression of RI induced ATG‑dependent autophagy in CRC cells via the Akt/mTOR/ULK1 pathway, suggesting that the upregulation of RI activity may constitute a novel approach for the treatment of human colorectal carcinoma.

Guo C, Liang C, Yang J, et al.
LATS2 inhibits cell proliferation and metastasis through the Hippo signaling pathway in glioma.
Oncol Rep. 2019; 41(5):2753-2761 [PubMed] Free Access to Full Article Related Publications
As a core kinase in the Hippo pathway, large tumor suppressor kinase 2 (LATS2) regulates cell proliferation, migration and invasion through numerous signaling pathways. However, its functions on cell proliferation, migration and invasion in glioma have yet to be elucidated. The present study revealed that LATS2 was downregulated in glioma tissues and cells, as determined by reverse transcription‑quantitative polymerase chain reaction and immunohistochemistry. In addition, Cell Counting Kit‑8, scratch wound healing and Transwell assays revealed that overexpression of LATS2 in U‑372 MG cells inhibited cell proliferation, migration and invasion. Furthermore, western blot analysis indicated that the expression levels of phosphorylated (p)‑yes‑associated protein and p‑tafazzin were increased in cells with LATS2 overexpression. These results indicated that LATS2 is a potential tumor suppressor, and downregulation of LATS2 in glioma may contribute to cancer progression.

Fan JJ, Hsu WH, Hung HH, et al.
Reduction in MnSOD promotes the migration and invasion of squamous carcinoma cells.
Int J Oncol. 2019; 54(5):1639-1650 [PubMed] Free Access to Full Article Related Publications
Reactive oxygen species (ROS) homeostasis is maintained at a higher level in cancer cells, which promotes tumorigenesis. Oxidative stress induced by anticancer drugs may further increase ROS to promote apoptosis, but can also enhance the metastasis of cancer cells. The effects of ROS homeostasis on cancer cells remain to be fully elucidated. In the present study, the effect of a reduction in manganese superoxide dismutase (MnSOD) on the migration and invasion of A431 cells was investigated. Our previous micro‑assay data revealed that the mRNA expression of MnSOD was higher in the invasive A431‑III cell line compared with that in the parental A431 cell line (A431‑P). In the present study, high protein levels of MnSOD and H2O2 production were observed in A431‑III cells; however, catalase protein levels were significantly lower in A431‑III cells compared with those in the A431‑P cell line. The knockdown of MnSOD increased H2O2 levels, enzyme activity, the mRNA levels of matrix metalloproteinase‑1, ‑2 and ‑9, and the migratory and invasive abilities of the cells. Inducing a reduction in H2O2 using diphenyleneiodonium (DPI) and N‑acetyl‑l‑cysteine decreased the migratory abilities of the cell lines, and DPI attenuated the migratory ability that had been increased by MnSOD small interfering RNA knockdown. Luteolin (Lu) and quercetin (Qu) increased the expression of catalase and reduced H2O2 levels, but without an observed change in the protein levels of MnSOD. Taken together, these data suggest that reduced MnSOD may induce ROS imbalance in cells and promote the metastatic ability of cancer cells. Lu and Qu may attenuate these processes and may be promising potential anticancer agents.

Guo Z, Zhang J, Fan L, et al.
Long Noncoding RNA (lncRNA) Small Nucleolar RNA Host Gene 16 (SNHG16) Predicts Poor Prognosis and Sorafenib Resistance in Hepatocellular Carcinoma.
Med Sci Monit. 2019; 25:2079-2086 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Long noncoding RNAs (lncRNAs) play important roles in cancer development and therapeutic resistance. However, the role of small nucleolar RNA host gene 16 (SNHG16) in the development of hepatocellular carcinoma (HCC) remains largely unknown. MATERIAL AND METHODS In situ hybridization (ISH) staining was performed to detect the expression level of SNHG16 in HCC tissues and adjacent non-cancerous tissues. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the level of SNHG16 in HCC samples, adjacent non-cancerous tissues and HCC cell lines. Transwell assay was performed to investigate the migration and invasion ability of HCC cells. Cell viability assays were performed to determine the ability of proliferation and sorafenib resistance of HCC cells. RESULTS We found that SNHG16 was upregulated in HCC tissues and cell lines and that it was negatively correlated with survival time in HCC patients. Univariate and multivariate analyses revealed that SNHG16 was a significant and independent predictor for the overall survival of HCC patients. Furthermore, downregulation of SNHG16 inhibited proliferation, migration, invasion, and sorafenib resistance in hepatocellular carcinoma cell lines. CONCLUSIONS Our findings revealed that lncRNA SNHG16 could be used as an oncogene to predict the outcome of hepatocellular carcinoma.

Fan B, Yang X, Li X, et al.
Photoacoustic-imaging-guided therapy of functionalized melanin nanoparticles: combination of photothermal ablation and gene therapy against laryngeal squamous cell carcinoma.
Nanoscale. 2019; 11(13):6285-6296 [PubMed] Related Publications
Multimodality therapy under imaging-guidance is significant to improve the accuracy of cancer treatment. In this study, a photoacoustic imaging (PAI)-guided anticancer strategy based on poly-l-lysine functionalized melanin nanoparticles (MNP-PLL) was developed to treat laryngeal squamous cell carcinoma (LSCC). As a promising alternative to traditional therapies for LSCC, MNP-PLL/miRNA nanoparticles were combined with photothermal ablation against primary tumors and miR-145-5p mediated gene therapy for depleting the metastatic potential of tumor cells. Furthermore, taking advantage of the photoacoustic properties of melanin, PAI guided therapy could optimize the time point of NIR irradiation to maximize the efficacy of photothermal therapy (PTT). The in vitro and in vivo results proved that the combined treatments displayed the most significant tumor suppression compared with monotherapy. By integrating thermo-gene therapies into a theranostic nanoplatform, the MNP-PLL/miR-145-5p nanoparticles significantly suppressed the LSCC progression, indicating their great potential use for cancer therapy.

Zhang Y, Li J, Yi K, et al.
Elevated signature of a gene module coexpressed with CDC20 marks genomic instability in glioma.
Proc Natl Acad Sci U S A. 2019; 116(14):6975-6984 [PubMed] Article available free on PMC after 15/09/2019 Related Publications
Genomic instability (GI) drives tumor heterogeneity and promotes tumor progression and therapy resistance. However, causative factors underlying GI and means for clinical detection of GI in glioma are inadequately identified. We describe here that elevated expression of a gene module coexpressed with CDC20 (CDC20-M), the activator of the anaphase-promoting complex in the cell cycle, marks GI in glioma. The CDC20-M, containing 139 members involved in cell proliferation, DNA damage response, and chromosome segregation, was found to be consistently coexpressed in glioma transcriptomes. The coexpression of these genes was conserved across multiple species and organ systems, particularly in human neural stem and progenitor cells. CDC20-M expression was not correlated with the morphological subtypes, nor with the recently defined molecular subtypes of glioma. CDC20-M signature was an independent and robust predictor for poorer prognosis in over 1,000 patients from four large databases. Elevated CDC20-M signature enabled the identification of individual glioma samples with severe chromosome instability and mutation burden and of primary glioma cell lines with extensive mitotic errors leading to chromosome mis-segregation. AURKA, a core member of CDC20-M, was amplified in one-third of CDC20-M-high gliomas with gene-dosage-dependent expression. MLN8237, a Food and Drug Administration-approved AURKA inhibitor, selectively killed temozolomide-resistant primary glioma cells in vitro and prolonged the survival of a patient-derived xenograft mouse model with a high-CDC20-M signature. Our findings suggest that application of the CDC20-M signature may permit more selective use of adjuvant therapies for glioma patients and that dysregulated CDC20-M members may provide a therapeutic vulnerability in glioma.

Xiao C, Wan X, Yu H, et al.
LncRNA‑AB209371 promotes the epithelial‑mesenchymal transition of hepatocellular carcinoma cells.
Oncol Rep. 2019; 41(5):2957-2966 [PubMed] Related Publications
The zinc finger protein Snail1 is an important factor in the regulation of the epithelial‑mesenchymal transition (EMT) of hepatocellular carcinoma (HCC) cells. The present study demonstrated that the expression of Snail1 in HCC tissues was significantly higher compared with its expression in tissues adjacent to primary sites, as determined via western blotting. Furthermore, the results of a dual luciferase assay revealed that hsa‑microRNA(miR)199a‑5p negatively regulated the protein expression of Snail1 by binding to its 3' untranslated region. However, in a comparative analysis of primary HCC and its metastatic tissues using reverse transcription‑quantitative polymerase chain reaction and western blotting, it was demonstrated that the expression of hsa‑miR199a‑5p and Snail1 in HCC metastatic tissues were significantly higher compared with primary lesions and an association between them identified that hsa‑miR199a‑5p lost its ability to negatively regulate Snail1. This result is contradictive to the fact that hsa‑miR199a‑5p inhibits the expression of the Snail1 protein. The present study hypothesized that the aberrant expression of long non‑coding RNA was the cause of hsa‑miR199a‑5p inactivation based on loss of function rather than a reduction in content. The data collected in the present study confirmed the hypothesis that AB209371 binds to hsa‑miR199a‑5p and weakened the inhibitory effect of hsa‑miR199a‑5p on Snail1 expression. In addition, an in vitro EMT model was established in the present study by inducing HCC cells with TGF‑β1. The results revealed that AB209371 silencing effectively reversed the hsa‑miR199a‑5p mediated inhibition of EMT by negatively regulating Snail1 protein expression. Therefore, AB209371 silencing in combination with hsa‑miR199a‑5p expression may serve as an effective means to inhibit EMT in HCC cells. The present study also revealed that hsa‑miR199a‑5p/Snail1 exhibits a dominant regulatory effect in the EMT of HCC cells via a Snail1 recovery experiment. In conclusion, to the best of our knowledge, the present study confirmed for the first time that the high expression of AB209371 is favorable for the EMT in HCC cells and may be a direct cause of hsa‑miR199a‑5p inactivation (an HCC metastasis suppressor). Additionally, AB209371 silencing combined with hsa‑miR199a‑5p overexpression may be an effective means to inhibit the metastasis of HCC and the EMT of HCC cells.

Zhao X, Fan J, Wu P, et al.
Chronic chemotherapy with paclitaxel nanoparticles induced apoptosis in lung cancer in vitro and in vivo.
Int J Nanomedicine. 2019; 14:1299-1309 [PubMed] Article available free on PMC after 15/09/2019 Related Publications
Aim: Paclitaxel (PTX) is an effective antitumor drug. Previous research demonstrated that paclitaxel nanoparticles (PTX-NPs) exhibited the greatest antitumor effect at 15 hours after light onset (15 HALO), but the mechanism in chronic chemotherapy is still unknown. In our study, we investigated whether PTX-NPs regulated Period2 (Per2) during chronic chemotherapy to induce apoptosis in vivo and in vitro.
Methods: To improve the antitumor effect and reduce organ damage induced by PTX treatment, PTX-NPs were prepared using a film dispersion method. Then, A549 cells were treated with PTX-NPs at 0, 5, 10, 15, and 20 HALO. An annexin/PI V-FITC apoptosis kit was measured for apoptosis, and PI was analyzed for cell cycle. The relative mechanism was detected by RT-PCR and Western blotting. Tumor volume and weight were measured to evaluate the antitumor effect of the PTX-NPs, and H&E staining was performed to assess organ damage.
Results: Cell cycle analysis demonstrated that PTX-NPs blocked cell cycle in G2 phase and that the ratio of cell death was significantly increased in A549 cells, while the ratios of cells in G2 phase and of apoptotic cells were highest at 15 HALO. Evaluation of in vivo antitumor activity revealed that PTX-NPs inhibited tumor growth and decreased tumor weight at 15 HALO. RT-PCR and Western blotting demonstrated that PTX-NPs upregulated Per2 mRNA and protein expression, and the highest Per2 expression was observed at 15 HALO in vivo and in vitro. Meanwhile, Bax mRNA and protein expression was upregulated, while Bcl-2 mRNA and protein expression was downregulated after PTX-NPs treatment in vivo. Moreover, H&E staining revealed that PTX-NPs reduced liver damage at 15 HALO.
Conclusion: PTX-NPs exhibited the most effective antitumor activity and reduced liver damage at 15 HALO through upregulation of Per2 expression to induce apoptosis in vivo and in vitro.

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