Research IndicatorsGraph generated 30 August 2019 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (8)
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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: STAT3 (cancer-related)
Glioma, the most common human primary brain tumor, is characterized by invasive capabilities and angiogenesis. Vasorin (VASN), a transmembrane protein, is reported to be associated with vascular injury repair and is overexpressed in some human tumors. However, its role in tumor progression and angiogenesis in glioma is unknown. In this study, VASN was shown to be overexpressed in high-grade gliomas, and the expression level correlated with tumor grade and microvessel density in glioma specimens. Glioma patients with high VASN expression had a shorter overall survival time. Knockdown of VASN in glioma cells by shRNA significantly inhibited the malignancy of glioma, including cell proliferation, colony formation, invasion, and sphere formation. Ectopic expression of VASN increased glioma progression in vitro. The expression of VASN correlated with the mesenchymal type of glioblastoma multiforme (GBM) subtyped by gene set enrichment analysis (GSEA). Our results showed that the concentration of VASN was increased in the conditioned medium (CM) from glioma cells with VASN overexpression, and the CM from glioma cells with knockdown or overexpressed VASN inhibited or promoted HUVEC migration and tubulogenesis in vitro, respectively. Glioma growth and angiogenesis were stimulated upon ectopic expression of VASN in vivo. The STAT3 and NOTCH pathways were found to be activated and inhibited by VASN overexpression. Our findings suggest that VASN stimulates tumor progression and angiogenesis in glioma, and, as such, represents a novel therapeutic target for glioma.
While the antiandrogen enzalutamide (Enz) extends the castration resistant prostate cancer (CRPC) patients' survival an extra 4.8 months, it might also result in some adverse effects via inducing the neuroendocrine differentiation (NED). Here we found that lncRNA-p21 is highly expressed in the NEPC patients derived xenograft tissues (NEPC-PDX). Results from cell lines and human clinical sample surveys also revealed that lncRNA-p21 expression is up-regulated in NEPC and Enz treatment could increase the lncRNA-p21 to induce the NED. Mechanism dissection revealed that Enz could promote the lncRNA-p21 transcription via altering the androgen receptor (AR) binding to different androgen-response-elements, which switch the EZH2 function from histone-methyltransferase to non-histone methyltransferase, consequently methylating the STAT3 to promote the NED. Preclinical studies using the PDX mouse model proved that EZH2 inhibitor could block the Enz-induced NED. Together, these results suggest targeting the Enz/AR/lncRNA-p21/EZH2/STAT3 signaling may help urologists to develop a treatment for better suppression of the human CRPC progression.
Ma QY, Li SY, Li XZ, et al.Long non-coding RNA DILC suppresses bladder cancer cells progression.
Gene. 2019; 710:193-201 [PubMed
] Related Publications
Accumulative researches have demonstrated the critical functions of long non-coding RNAs (lncRNAs) in the progression of malignant tumors, including bladder cancer (BC). Our previous studies showed that lnc-DILC was an important tumor suppressor gene in both liver cancer and colorectal cancer. However, the role of lnc-DILC in BC remains to be elucidated. In the present study, we for first found that lnc-DILC was downregulated in human bladder cancer tissues. Lnc-DILC overexpression suppressed the proliferation, metastasis and expansion of bladder cancer stem cells (CSCs). Mechanically, lnc-DILC suppressed BC cells progression via STAT3 pathway. Special STAT3 inhibitor S3I-201 diminished the discrepancy of growth, metastasis and self-renewal ability between lnc-DILC-overexpression BC cells and their control cells, which further confirmed that STAT3 was acquired for lnc-DILC-disrupted BC cell growth, metastasis and self-renewal. Taken together, our results suggest that lnc-DILC is a novel bladder tumor suppressor and indicate that lnc-DILC inhibits BC progression via inactivating STAT3 signaling.
Long noncoding RNAs (lncRNAs) have emerged as new regulatory molecules implicated in diverse biological processes, including therapeutic resistance. However, the mechanisms underlying lncRNA-mediated temozolomide (TMZ) resistance in glioblastoma (GBM) remain largely unknown. To illustrate the role of lncRNA in TMZ resistance, we induce TMZ-resistant GBM cells, perform a lncRNA microarray of the parental and TMZ-resistant cells, and find an unreported lncRNA in GBM, lnc-TALC (temozolomide-associated lncRNA in glioblastoma recurrence), correlated with TMZ resistance via competitively binding miR-20b-3p to facilitate c-Met expression. A phosphorylated AKT/FOXO3 axis regulated lnc-TALC expression in TMZ-resistant GBM cells. Furthermore, lnc-TALC increased MGMT expression by mediating the acetylation of H3K9, H3K27 and H3K36 in MGMT promoter regions through the c-Met/Stat3/p300 axis. In clinical patients, lnc-TALC is required for TMZ resistance and GBM recurrence. Our results reveal that lnc-TALC in GBM could serve as a therapeutic target to overcome TMZ resistance, enhancing the clinical benefits of TMZ chemotherapy.
Cai G, Yu W, Song D, et al.Discovery of fluorescent coumarin-benzo[b]thiophene 1, 1-dioxide conjugates as mitochondria-targeting antitumor STAT3 inhibitors.
Eur J Med Chem. 2019; 174:236-251 [PubMed
] Related Publications
STAT3 has been extensively studied as a potential antitumor target. Though studies on regulating STAT3 mainly focus on the inhibition of STAT3 phosphorylation at Tyr705 residue, the phosphorylation at Ser727 residue of STAT3 protein is also closely associated with the mitochondrial import of STAT3 protein. N, N-diethyl-7-aminocoumarin is a fluorescent mitochondria-targeting probe. In this study, a series of STAT3 inhibitors were developed by connecting N, N-diethyl-7-aminocoumarin fluorophore with benzo [b]thiophene 1, 1-dioxide moiety. All designed compounds displayed potent anti-proliferative activity against cancer cells. The representative compound 7a was mainly accumulated in mitochondria visualized by its fluorescence. STAT3 phosphorylation was inhibited by compound 7a at both Tyr705 and Ser727 residues. Compound 7a inhibited STAT3 phosphorylation whereas had no influence on the phosphorylation levels of STAT1, JAK2, Src and Erk1/2, indicating good selectivity of compound 7a. Moreover, compound 7a down-regulated the expression of STAT3 target genes Bcl-2 and Cyclin D1, increased ROS production and remarkably reduced the mitochondrial membrane potential to induce mitochondrial apoptotic pathway. Furthermore, compound 7ain vivo suppressed breast cancer 4T1 implanted tumor growth. Taken together, these results highlighted that compound 7a might be a promising mitochondria-targeting STAT3 inhibitor for cancer therapy.
Colorectal cancer (CRC) is one of the most common types of malignant tumor. Many genetic factors have been proved to show high association with the occurrence and development of CRC and many mutations are detected in CRC. PTPN4/PTP-MEG1 is a widely expressed non-receptor protein tyrosine phosphatase. Over the past three decades, PTPN4 has been demonstrated in the literature to participate in many biological processes. In this study, we identified a nonsense mutation of PTPN4 with a mutation ratio of 90.90% from 1 case of rectal cancer, leading to loss of function in PTPN4 gene. Several somatic mutations occurred in 5/137 rectal cancer samples from The Cancer Genome Atlas Rectum Adenocarcinoma (TCGA READ) database. Interestingly, we found that PTPN4 negative cytoplasm staining was more prone to lymphatic metastasis (N = 50, P = 0.0153) and low expression of PTPN4 in rectal cancer was highly associated with poor prognosis. Overexpression of PTPN4 suppressed the cell growth, and moreover, the loss of PTPN4 accelerated cell growth and boosted clonogenicity of CRC cells. Furthermore, we revealed that the deletion of PTPN4 promoted the tumor formation of NCM460 cells in vivo. In terms of the molecular mechanism, we demonstrated that PTPN4 dephosphorylates pSTAT3 at the Tyr705 residue with a direct interaction and suppresses the transcriptional activity of STAT3. In summary, our study revealed a novel mechanism that the tumorigenesis of colorectal cancer might be caused by the loss of PTPN4 through activating STAT3, which will broaden the therapy strategy for anti-rectal cancer in the future.
PURPOSE: The protein tyrosine phosphatase PTPN2 dephosphorylates several tyrosine kinases in cancer-related signalling pathways and is thought to be a tumour suppressor. As PTPN2 is not frequently studied in breast cancer, we aimed to explore the role of PTPN2 and the effects of its loss in breast cancer.
METHODS: Protein expression and gene copy number of PTPN2 were analysed in a cohort of pre-menopausal breast cancer patients with immunohistochemistry and droplet digital PCR, respectively. PTPN2 was knocked down in three cell lines, representing different breast cancer subtypes, with siRNA transfection. Several proteins related to PTPN2 were analysed with Western blot.
RESULTS: Low PTPN2 protein expression was found in 50.2% of the tumours (110/219), gene copy loss in 15.4% (33/214). Low protein expression was associated with a higher relapse rate in patients with Luminal A and HER2-positive tumours, but not triple-negative tumours. In vitro studies further suggested a subtype-specific role of PTPN2. Knockdown of PTPN2 had no effect on the triple-negative cell line, whilst knockdown in MCF7 inhibited phosphorylation of Met and promoted that of Akt. Knockdown in SKBR3 led to increased Met phosphorylation and decreased Erk phosphorylation as well as EGF-mediated STAT3 activation.
CONCLUSION: We confirm previous studies showing that the PTPN2 protein is lost in half of the breast cancer cases and gene deletion occurs in 15-18% of the cases. Furthermore, the results suggest that the role of PTPN2 is subtype-related and should be further investigated to assess how this could affect breast cancer prognosis and treatment response.
Cancer stem cells (CSCs) are known to mediate metastasis and recurrence and are therefore a promising therapeutic target. In this study, we found that dihydrotanshinone (DHTS) inhibits CSC formation. DHTS inhibited mammosphere formation in a dose-dependent manner and showed significant tumor growth inhibition in a xenograft model. This compound reduced the CD44
STAT3 is an oncoprotein overexpressed in different types of tumors, including prostate cancer (PCa), and its activity is modulated by a variety of post-translational modifications (PTMs). Prostate cancer represents the most common cancer diagnosed in men, and each phase of tumor progression displays specific cellular conditions: inflammation is predominant in tumor's early stage, whereas oxidative stress is typical of clinically advanced PCa. The aim of this research is to assess the correspondence between the stimulus-specificity of STAT3 PTMs and definite STAT3-mediated transcriptional programs, in order to identify new suitable pharmacological targets for PCa treatment. Experiments were performed on less-aggressive LNCaP and more aggressive DU-145 cell lines, simulating inflammatory and oxidative-stress conditions. Cellular studies confirmed pY705-STAT3 as common denominator of all STAT3-mediated signaling. In addition, acK685-STAT3 was found in response to IL-6, whereas glutC328/542-STAT3 and pS727-STAT3 occurred upon tert-butyl hydroperoxyde (tBHP) treatment. Obtained results also provided evidence of an interplay between STAT3 PTMs and specific protein interactors such as P300 and APE1/Ref-1. In accordance with these outcomes, mRNA levels of STAT3-target genes seemed to follow the differing STAT3 PTMs. These results highlighted the role of STAT3 and its PTMs as drivers in the progression of PCa.
The inactivation of tumor suppressor gene positive regulatory domain containing I (PRDM1) and activation of signal transducer and activator of transcription 3 (STAT3) have been detected in the majority of extranodal NK/T‑cell lymphoma, nasal type (EN‑NK/T‑NT) cases. In the present study, their association with and effects on the clinicopathologic features of EN‑NK/T‑NT are described. PRDM1 was revealed to be expressed in 19 out of 58 patients (32.8%) with EN‑NK/T‑NT, and phosphorylated STAT3 was overexpressed in 42 out of 58 (72.4%). Oncogenic pathways were investigated by NanoString encounter technology in 5 PRDM1(+) and 5 PRDM1(‑) EN‑NK/T‑NT specimens. Multiple oncogenic pathways involved in cell apoptosis, cellcycle (CC) and angiogenesis were discriminately activated in EN‑NK/T‑NT cases, and in PRDM1(+) cases in particular. The sustained activation of the Janus kinase 3 (JAK)/STAT3 pathway was more pronounced. In addition, missense mutations in the SRC homology 2 domain of STAT3 were detected in 7 out of 37 EN‑NK/T‑NT cases (18.92%), and the acquired mutation was related to the activation of the JAK3/STAT3 pathway. The downregulation of PRDM1 and upregulation of phospho‑STAT3 (Tyr705) were associated with angiocentric infiltration of EN‑NK/T‑NT (P=0.039). Notably, the prognosis of patients in the PRDM1(+)/STAT3 [mutated (mut‑)] group was considerably improved than that of patients in the STAT3(mut+)/PRDM(‑) group (P=0.037). In addition, the inhibition of NK/T cell lymphoma cell lines by Stattic and tofacitinib could suppress cell proliferation by inducing cell apoptosis or arresting the CC. The present results revealed that the JAK3/STAT3 oncogenic pathway and PRDM1 expression could stratify clinicopathologic features of EN‑NK/T‑NT. The inhibition of the JAK3/STAT3 pathway may serve as a treatment option for EN‑NK/T‑NT.
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.
Pituitary adenoma is one of the most common tumors in the neuroendocrine system. This study investigated the effects of long non-coding RNAs (lncRNAs) highly up-regulated in liver cancer (HULC) on rat secreting pituitary adenoma GH3 cell viability, migration, invasion, apoptosis, and hormone secretion, as well as the underlying potential mechanisms. Cell transfection and qRT-PCR were used to change and measure the expression levels of HULC, miR-130b, and FOXM1. Cell viability, migration, invasion, and apoptosis were assessed using trypan blue staining assay, MTT assay, two-chamber transwell assay, Guava Nexin assay, and western blotting. The concentrations of prolactin (PRL) and growth hormone (GH) in culture supernatant of GH3 cells were assessed using ELISA. The targeting relationship between miR-130b and FOXM1 was verified using dual luciferase activity. Finally, the expression levels of key factors involved in PI3K/AKT/mTOR and JAK1/STAT3 pathways were evaluated using western blotting. We found that HULC was highly expressed in GH3 cells. Overexpression of HULC promoted GH3 cell viability, migration, invasion, PRL and GH secretion, as well as activated PI3K/AKT/mTOR and JAK1/STAT3 pathways. Knockdown of HULC had opposite effects and induced cell apoptosis. HULC negatively regulated the expression of miR-130b, and miR-130b participated in the effects of HULC on GH3 cells. FOXM1 was a target gene of miR-130b, which was involved in the regulation of GH3 cell viability, migration, invasion, and apoptosis, as well as PI3K/AKT/mTOR and JAK1/STAT3 pathways. In conclusion, HULC tumor-promoting roles in secreting pituitary adenoma might be via down-regulating miR-130b, up-regulating FOXM1, and activating PI3K/AKT/mTOR and JAK1/STAT3 pathways.
Hua L, Wang G, Wang Z, et al.Activation of STAT1 by the FRK tyrosine kinase is associated with human glioma growth.
J Neurooncol. 2019; 143(1):35-47 [PubMed
] Related Publications
PURPOSE: Glioma is a highly aggressive and lethal brain tumor. Signal transducers and activators of transcription (STAT) pathway are widely implicated in glioma carcinogenesis. Our previous study found that the Fynrelated kinase (FRK) gene, plays as a tumor suppressor in the development and progression of glioma. This study aimed to investigate the role of FRK in the activation pathway of STATs and its effect on the growth of glioma.
METHODS: The U251 and U87 cells with stable FRK overexpression were generated by lentivirus technique. The effects of FRK on the related proteins of STAT signaling pathway were detected by western blotting. Coimmunoprecipitation was used to detect the association of FRK and STAT1. The effects of STAT1 on the proliferation of glioma cells were detected by CCK8 or Edu cell proliferation assays. The expressions and correlation of FRK and p-STAT1 in glioma tissues were detectd by western blotting or immunohistochemistry. The effect of FRK on the growth of glioma was investigated in vivo mouse model.
RESULTS: The level of p-JAK2 and p-STAT1 increased after FRK overexpression, while they decreased after FRK downregulation both in U251 and U87 cells. However, FRK had no effect on STAT3 phosphorylation. FRK-induced STAT1 activation was not dependent on JAK2. FRK associated with STAT1, induced STAT1 nuclear translocation and regulated the expressions of STAT1-related target genes. STAT1 overexpression suppressed the proliferation of glioma cells. In contrast, STAT1 knockdown by siRNA promoted glioma cell growth. Importantly, down-regulation of STAT1 partially attenuated FRK-induced growth suppression. The clinical sample-based study indicated that the expression of FRK was significantly correlated with the expression of p-STAT1. FRK significantly inhibited glioma tumor growth in vivo.
CONCLUSIONS: Our findings highlighted a critical role of FRK in tumor suppression ability through promoting STAT1 activation, and provided a potential therapeutic target for glioma.
Hwang ST, Kim C, Lee JH, et al.Cycloastragenol can negate constitutive STAT3 activation and promote paclitaxel-induced apoptosis in human gastric cancer cells.
Phytomedicine. 2019; 59:152907 [PubMed
] Related Publications
BACKGROUND: Cycloastragenol (CAG), a triterpene aglycone is commonly prescribed for treating hypertension, cardiovascular disease, diabetic nephropathy, viral hepatitis, and various inflammatory-linked diseases.
HYPOTHESIS: We investigated CAG for its action on signal transducer and activator of transcription 3 (STAT3) activation cascades, and its potential to sensitize gastric cancer cells to paclitaxel-induced apoptosis.
METHODS: The effect of CAG on STAT3 phosphorylation and other hallmarks of cancer was deciphered using diverse assays in both SNU-1 and SNU-16 cells.
RESULTS: We observed that CAG exhibited cytotoxic activity against SNU-1 and SNU-16 cells to a greater extent as compared to normal GES-1 cells. CAG predominantly caused negative regulation of STAT3 phosphorylation at tyrosine 705 through the abrogation of Src and Janus-activated kinases (JAK1/2) activation. We noted that CAG impaired translocation of STAT3 protein as well as its DNA binding activity. It further decreased cellular proliferation and mediated its anticancer effects predominantly by causing substantial apoptosis rather than autophagy. In addition, CAG potentiated paclitaxel-induced anti-oncogenic effects in gastric tumor cells.
CONCLUSIONS: Our results indicate that CAG can function to impede STAT3 activation in human gastric tumor cells and therefore it may be a suitable candidate agent for therapy of gastric cancer.
Quercetin (QE) is an attractive natural compound for cancer prevention due to its beneficial anti-oxidative and anti-proliferative effects. However, QE is poorly soluble in water and slightly soluble in oil, which results in its low oral bioavailability and limits its application in the clinic. The aim of this study was to prepare QE nanocrystals (QE-NCs) with improved solubility and high drug loading, furthermore, the size-dependent anti-cancer effects of QE-NCs were studied. We prepared QE-NCs with three different particle sizes by wet milling, then, cell proliferation, migration and invasion were studied in A549 cells. The QE-NCs had antitumor effects in a dose- and size-dependent manner. Compared with the large particles, the small particles had a strong inhibitory impact on cell biological effects (
Liu X, Chen H, Hou Y, et al.Adaptive EGF expression sensitizes pancreatic cancer cells to ionizing radiation through activation of the cyclin D1/P53/PARP pathway.
Int J Oncol. 2019; 54(4):1466-1480 [PubMed
] Related Publications
It is well-known that the activation status of the P53, signal transducer and activator of transcription (Stat)3 and nuclear factor (NF)‑κB signaling pathways determines the radiosensitivity of cancer cells. However, the function of these pathways in radiosensitive vs radioresistant cancer cells remains elusive. The present study demonstrated that adaptive expression of epidermal growth factor (EGF) following exposure to ionizing radiation (IR) may induce radiosensitization of pancreatic cancer (PC) cells through induction of the cyclin D1/P53/poly(ADP‑ribose) polymerase pathway. By contrast, adaptively expressed interleukin (IL)‑6 and insulin‑like growth factor (IGF)‑1 may promote radioresistance of PC cells, likely through activation of the Stat3 and NF‑κB pathways. In addition, cyclin D1 and survivin, which are specifically expressed in the G1/S and G2/M phase of the cell cycle, respectively, are mutually exclusive in radiosensitive and radioresistant PC cells, while Bcl‑2 and Bcl‑xL expression does not differ between radiosensitive and radioresistant PC cells. Therefore, adaptively expressed EGF and IL‑6/IGF‑1 may alter these pathways to promote the radiosensitivity of PC cancers. The findings of the present study highlight potential makers for the evaluation of radiosensitivity and enable the development of effective regimens for cancer radiotherapy.
BACKGROUND: The cisplatin-resistance is still a main course for chemotherapy failure of lung cancer patients. Cisplatin-resistant cancer cells own higher malignance and exhibited increased metastatic ability, but the mechanism is not clear. In this study, we investigated the effects of Ataxia Telangiectasia Mutated (ATM) on lung cancer metastasis.
MATERIALS AND METHODS: Cisplatin-resistant A549CisR and H157CisR cell line were generated by long-term treating parental A549 and H157 cells (A549P and H157P) with cisplatin. Cell growth, cell migration and cell invasion were determined. Gene expressions were determined by Western Blot and qPCR. Tumor metastasis was investigated using a xenograft mouse model.
RESULTS: The IC50 of the cisplatin-resistant cells (A549CisR and H157CisR cells) to cisplatin was 6-8 higher than parental cells. The A549CisR and H157CisR cells expressed lower level of E-cadherin and higher levels of N-cadherin, Vimentin and Snail compared to the parental A549P and H157P cells, and exhibited stronger capabilities of metastatic potential compared to the parental cells. The ATM expression was upregulated in A549CisR and H157CisR cells and cisplatin treatment also upregulated expression of ATM in parental cells, The inhibition of ATM by using specific ATM inhibitor CP466722 or knock-down ATM by siRNA suppressed Epithelial-to-Mesenchymal transition (EMT) and metastatic potential of A549CisR and H157CisR cells. These data suggest that ATM mediates the cisplatin-resistance in lung cancer cells. Expressions of JAK
CONCLUSIONS: Our results show that ATM regulates PD-L1 expression through activation of JAK/STAT3 signaling in cisplatin-resistant cells. Overexpression of ATM contributes to cisplatin-resistance in lung cancer cells. Inhibition of ATM reversed EMT and inhibited cell invasion and tumor metastasis. Thus, ATM may be a potential target for the treatment of cisplatin-resistant lung cancer.
Gerbe A, Alame M, Dereure O, et al.Systemic, primary cutaneous, and breast implant-associated ALK-negative anaplastic large-cell lymphomas present similar biologic features despite distinct clinical behavior.
Virchows Arch. 2019; 475(2):163-174 [PubMed
] Related Publications
Despite distinct clinical presentation and outcome, systemic, primary cutaneous, and breast implant-associated anaplastic large cell lymphomas (S-, PC-, BI-ALCL) ALK-negative (ALK-) show similar histopathological features including the presence of the "hallmark" cells with horseshoe-shaped nuclei and CD30 protein expression. The purpose was to better characterize these three entities using immunohistochemistry and FISH (Fluorescent in situ hybridization) to identify biomarkers differently expressed and that might be involved in their pathogenesis. Twenty-two S-ALCL ALK-, 13 PC-ALCL, and 2 BI-ALCL were included. Cases were tested for P53, P63, MUM1, MYC, GATA3, p-STAT3, PD1, and PDL1 protein expression and DUP22, TP53, TP63, MYC, and PDL1 chromosomal aberrations. As expected, S-ALCL ALK- patients had adverse outcome compare to PC and BI-ALCL. No difference was observed between the three groups concerning protein expression except for MUM1 that was significantly more frequently expressed in S-ALCL ALK- compared to PC-ALCL. In particular, constitutive activation of the STAT3 pathway and PDL1/PD1 immune-checkpoint expression was present in the three entities. TP53 deletion and PDL1 gene amplification were the commonest cytogenetic alterations and were present in the three entities. None of the studied biological parameters was associated with prognosis. Despite distinct clinical behavior, S-ALCL ALK-, PC-ALCL, and BI-ALCL share similar biological features. Larger series should be investigated with the current approach to determine more precisely the activity and the prognostic value of these biomarkers and pathways in each group.
BACKGROUND: The tumour microenvironment is a critical regulator of malignant cancer progression. While endothelial cells have been widely studied in the context of tumour angiogenesis, their role as modulators of cancer cell invasion and migration is poorly understood.
METHODS: We have investigated the influence of endothelial cells on the invasive and migratory behaviour of human cancer cells in vitro.
RESULTS: Upon exposure to culture supernatants of endothelial cells, distinct cancer cells, such as SK-BR-3 cells, showed significantly increased invasion and cell migration concomitant with changes in cell morphology and gene expression reminiscent of an epithelial-mesenchymal transition (EMT). Interestingly, the pro-migratory effect on SK-BR-3 cells was significantly enhanced by supernatants obtained from subconfluent, proliferative endothelial cells rather than from confluent, quiescent endothelial cells. Systematically comparing the supernatants of subconfluent and confluent endothelial cells by quantitative MS proteomics revealed eight candidate proteins that were secreted at significantly higher levels by confluent endothelial cells representing potential inhibitors of cancer cell migration. Among these proteins, nidogen-1 was exclusively expressed in confluent endothelial cells and was found to be necessary and sufficient for the inhibition of SK-BR-3 cell migration. Indeed, SK-BR-3 cells exposed to nidogen-1-depleted endothelial supernatants showed increased promigratory STAT3 phosphorylation along with increased cell migration. This reflects the situation of enhanced SK-BR-3 migration upon stimulation with conditioned medium from subconfluent endothelial cells with inherent absence of nidogen-1 expression.
CONCLUSION: The identification of nidogen-1 as an endothelial-derived inhibitor of migration of distinct cancer cell types reveals a novel mechanism of endothelial control over cancer progression.
Wei C, Yang C, Wang S, et al.Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis.
Mol Cancer. 2019; 18(1):64 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Tumor-associated macrophages (TAMs) are major components of tumor microenvironment that frequently associated with tumor metastasis in human cancers. Circulating tumor cell (CTC), originating from primary tumor sites, is considered to be the precursors of tumor metastasis. However, the regulatory mechanism of TAMs in CTC-mediated tumor metastasis still remains unclear.
METHODS: Immunohistochemical staining was used to detect the macrophages infiltration (CD68 and CD163), epithelial-mesenchymal transition (EMT) markers (E-cadherin and Vimentin) expression in serial sections of human colorectal cancer (CRC) specimens. Then, the correlations between macrophages infiltration and clinicopathologic features, mesenchymal CTC ratio, and patients' prognosis were analyzed. A co-culture assay in vitro was used to evaluate the role of TAMs on CRC EMT, migration and invasion, and ELISA, luciferase reporter assay and CHIP were performed to uncover the underlying mechanism. Furthermore, an in vivo model was carried out to confirm the effect of TAMs on mesenchymal CTC-mediated metastasis.
RESULTS: Clinically, CD163
CONCLUSIONS: Our data indicates that TAMs induce EMT program to enhance CRC migration, invasion, and CTC-mediated metastasis by regulating the JAK2/STAT3/miR-506-3p/FoxQ1 axis, which in turn leads to the production of CCL2 that promote macrophage recruitment, revealing a new cross-talk between immune cells and tumor cells in CRC microenvironment.
Wang Z, Shen J, Sun W, et al.Antitumor activity of Raddeanin A is mediated by Jun amino-terminal kinase activation and signal transducer and activator of transcription 3 inhibition in human osteosarcoma.
Cancer Sci. 2019; 110(5):1746-1759 [PubMed
] Free Access to Full Article Related Publications
Osteosarcoma is the most common primary malignant bone tumor. Raddeanin A (RA) is an active oleanane-type triterpenoid saponin extracted from the traditional Chinese herb Anemone raddeana Regel that exerts antitumor activity against several cancer types. However, the effect of RA on osteosarcoma remains unclear. In the present study, we showed that RA inhibited proliferation and induced apoptosis of osteosarcoma cells in a dose- and time-dependent way in vitro and in vivo. RA treatment resulted in excessive reactive oxygen species (ROS) generation and JNK and ERK1/2 activation. Apoptosis induction was evaluated by the activation of caspase-3, caspase-8, and caspase-9 and poly-ADP ribose polymerase (PARP) cleavage. RA-induced cell death was significantly restored by the ROS scavenger glutathione (GSH), the pharmacological inhibitor of JNK SP600125, or specific JNK knockdown by shRNA. Additionally, signal transducer and activator of transcription 3 (STAT3) activation was suppressed by RA in human osteosarcoma, and this suppression was restored by GSH, SP600125, and JNK-shRNA. Further investigation showed that STAT3 phosphorylation was increased after JNK knockdown. In a tibial xenograft tumor model, RA induced osteosarcoma apoptosis and notably inhibited tumor growth. Taken together, our results show that RA suppresses proliferation and induces apoptosis by modulating the JNK/c-Jun and STAT3 signaling pathways in human osteosarcoma. Therefore, RA may be a promising candidate antitumor drug for osteosarcoma intervention.
Cui Z, Liu Z, Zeng J, et al.TRIM59 promotes gefitinib resistance in EGFR mutant lung adenocarcinoma cells.
Life Sci. 2019; 224:23-32 [PubMed
] Related Publications
AIMS: The relationship between TRIM59 and drug resistance is elusive despite of its multiple uncovered roles in human cancers. Here we aimed to characterize the expression status of TRIM59 in gefitinib-resistant EGFR mutant lung adenocarcinoma cells and elucidate its mechanism underlying the drug resistance.
MAIN METHODS: Gefitinib-resistant cell lines were established by progressive dosage. Relative expression of TRIM59 was determined by both real-time PCR and Western blot. Target gene knockdown was achieved by specific shRNAs. Cell viability was measured by MTT assay. Cell apoptosis was analyzed by flow cytometry with Annexin V/7-AAD double staining. Cell proliferation was determined by clonogenic formation assay. Migration and invasion capacities were detected using transwell chamber assay. Direct interaction between TRIM59 and STAT3 was analyzed by co-immunoprecipitation assay.
KEY FINDINGS: We first observed overexpression of TRIM59 in gefitinib-resistant EGFR mutant lung adenocarcinoma cells. ShRNA-mediated knockdown of TRIM59 significantly inhibited cell viability and stimulated apoptosis. Meanwhile, TRIM59-deficiency suppressed cell migration and invasion. We further identified the interaction between TRIM59 and STAT3. TRIM59-deficiency remarkably impaired the activation of STAT3 signaling. STAT3-specific shRNAs significantly re-sensitized TRIM59-proficient EGFR mutant lung adenocarcinoma cells to gefitinib.
SIGNIFICANCE: Our data characterized aberrant TRIM59 overexpression in gefitinib-resistance EGFR mutant lung adenocarcinoma cells, and indicated the potential involvement of TRIM59-STAT3 signaling in the occurrence of gefitinib-resistance.
Lawrenson K, Song F, Hazelett DJ, et al.Genome-wide association studies identify susceptibility loci for epithelial ovarian cancer in east Asian women.
Gynecol Oncol. 2019; 153(2):343-355 [PubMed
] Related Publications
OBJECTIVE: Genome-wide association studies (GWASs) for epithelial ovarian cancer (EOC) have focused largely on populations of European ancestry. We aimed to identify common germline variants associated with EOC risk in Asian women.
METHODS: Genotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations.
RESULTS: At chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR] = 1.34, P = 8.7 × 10
CONCLUSION: While some risk loci were shared between East Asian and European populations, others were population-specific, indicating that the landscape of EOC risk in Asian women has both shared and unique features compared to women of European ancestry.
BACKGROUND: Glioblastoma multiforme (GBM) is the most common and aggressive form of astrocytoma among adult brain tumors. Multiple studies have shown that long non-coding RNAs (lncRNAs) play important roles in acting as molecular sponge for competing with microRNAs (miRNAs) to regulate downstream molecules in tumor progression. We previously reported that miR155 host gene (miR155HG), an lncRNA, and its derivative miR-155 promote epithelial-to-mesenchymal transition in glioma. However, the other biological functions and mechanisms of miR155HG sponging miRNAs have been unknown. Considering ANXA2 has been generally accepted as oncogene overexpressed in a vast of cancers correlated with tumorigenesis, which might be the target molecule of miR155HG sponging miRNA via bioinformatics analysis. We designed this study to explore the interaction of miR155HG and ANXA2 to reveal the malignancy of them in GBM development.
METHODS: The expression of miR155HG was analyzed in three independent databases and clinical GBM specimens. Bioinformatics analysis was performed to assess the potential tumor-related functions of miR155HG. The interaction of miR155HG and miR-185 and the inhibition of ANXA2 by miR-185 were analyzed by luciferase reporter experiments, and biological effects in GBM were explored by colony formation assays, EDU cell proliferation assays, flow cytometric analysis and intracranial GBM mouse model. Changes in protein expression were analyzed using western blot. We examined the regulatory mechanism of ANXA2 on miR155HG in GBM by gene expression profiling analysis, double immunofluorescence staining, chromatin immunoprecipitation and luciferase reporter assays.
RESULTS: We found that miR155HG was upregulated in GBM tissues and cell lines. Bioinformatic analyses of three GBM databases showed that miR155HG expression levels were closely associated with genes involved in cell proliferation and apoptosis. Knocking down miR155HG suppressed GBM cell proliferation in vitro, induced a G1/S-phase cell cycle arrest, and increased apoptosis. We also found that miR155HG functions as a competing endogenous RNA for miR-185. Moreover, miR-185 directly targets and inhibits ANXA2, which exhibits oncogenic functions in GBM. We also found that ANXA2 promoted miR155HG expression via STAT3 phosphorylation.
CONCLUSION: Our results demonstrated that overexpressed miR155HG in GBM can sponge miR-185 to promote ANXA2 expression, and ANXA2 stimulates miR155HG level through phosphorylated STAT3 binding to the miR155HG promoter. We establish the miR155HG/miR185/ANXA2 loop as a mechanism that underlies the biological functions of miR155HG and ANXA2 in GBM and further suggest this loop may serve as a therapeutic target and/or prognostic biomarker for GBM.
MicroRNAs (miRNAs) are pivotal regulators of the progression of carcinogenesis and negatively regulate the expression of tumour‑associated genes. Downregulation of miR‑124 expression has been demonstrated in various human cancer tissues, wherein miR‑124 serves as a tumour suppressor by targeting oncogenes. However, its function and underlying mechanism of action remain unclear in breast cancer. In the present study, the tissue‑specific expression of miR‑124 was detected in 10 paired triple‑negative breast cancer and normal tissues, and its inhibitory effects on cell growth and invasion were evaluated in vitro and in vivo. Bioinformatics analysis identified signal transducer and activator of transcription 3 (STAT3), a well‑known oncogene in breast cancer, as the potential target. Upregulation of miR‑124 expression decreased STAT3 mRNA and protein levels in breast cancer cells and the relative luciferase activity. Rescue experiments revealed that the transfection of a STAT3 expression plasmid reversed the inhibitory effect of miR‑124 on the proliferation and invasion of MDA‑MB‑468 cells. These data demonstrate that miR‑124 serves vital roles in the suppression of triple‑negative breast cancer via inhibition of cell proliferation and invasion through STAT3. These results highlight the potential role of miR‑124 as a diagnostic or therapeutic target in patients with breast cancer.
Lu X, Yu Y, Tan SLong non-coding XIAP-AS1 regulates cell proliferation, invasion and cell cycle in colon cancer.
Artif Cells Nanomed Biotechnol. 2019; 47(1):767-775 [PubMed
] Related Publications
Colon cancer is one of the most commonly diagnosed and deadly cancers worldwide. Further understanding of the biological mechanisms is important for exploring the molecular biomarkers and therapeutic targets of this disease. Dysregulation of long non-coding RNAs (lncRNAs) has been reported to be associated with the development and progression of various cancers. XIAP-AS1 is a novel lncRNA, which can regulate apoptosis in gastric cancer cells. However, the role of XIAP-AS1 in colorectal cancer (CRC) remains unclear. In this study, we found that XIAP-AS1 expression was significantly increased in CRC tissues and its expression showed a positive correlation with TNM stage and cumulative survival rate of CRC. To investigate whether XIAP-AS1 regulates the progression of CRC, we knocked down its expression in several CRC cell lines. CCK-8 assays showed that XIAP-AS1 knockdown remarkably suppressed CRC cell growth and arrested the cell cycle at the G0/G1 phase (flow cytometric analysis). Furthermore, XIAP-AS1 knockdown also remarkably blocked cell invasion of colon cancer cells by regulating the expression of EMT markers, such as E-cadherin, ZO-1, vimentin, and N-cadherin. Importantly, we found that XIAP-AS1 knockdown significantly reduced STAT3 phosphorylation. Overall, this study suggests that lncRNA XIAP-AS1 might serve as a potential oncogene for colon cancer.
Buendia Duque M, Pinheiro KV, Thomaz A, et al.Combined Inhibition of HDAC and EGFR Reduces Viability and Proliferation and Enhances STAT3 mRNA Expression in Glioblastoma Cells.
J Mol Neurosci. 2019; 68(1):49-57 [PubMed
] Related Publications
Changes in expression of histone deacetylases (HDACs), which epigenetically regulate chromatin structure, and mutations and amplifications of the EGFR gene, which codes for the epidermal growth factor receptor (EGFR), have been reported in glioblastoma (GBM), the most common and malignant type of brain tumor. There are likely interplays between HDACs and EGFR in promoting GBM progression, and HDAC inhibition can cooperate with EGFR blockade in reducing the growth of lung cancer cells. Here, we found that either HDAC or EGFR inhibitors dose-dependently reduced the viability of U87 and A-172 human GBM cells. In U87 cells, the combined inhibition of HDACs and EGFR was more effective than inhibiting either target alone in reducing viability and long-term proliferation. In addition, HDAC or EGFR inhibition, alone or combined, led to G0/G1 cell cycle arrest. The EGFR inhibitor alone or combined with HDAC inhibition increased mRNA expression of the signal transducer and activator of transcription 3 (STAT3), which can act either as an oncogene or a tumor suppressor in GBM. These data provide early evidence that combining HDAC and EGFR inhibition may be an effective strategy to reduce GBM growth, through a mechanism possibly involving STAT3.
Tao X, Zuo Q, Ruan H, et al.Argininosuccinate synthase 1 suppresses cancer cell invasion by inhibiting STAT3 pathway in hepatocellular carcinoma.
Acta Biochim Biophys Sin (Shanghai). 2019; 51(3):263-276 [PubMed
] Related Publications
Metastasis is the main reason for high recurrence and poor survival of hepatocellular carcinoma (HCC). The molecular mechanism underlying HCC metastasis remains unclear. In this study, we found that argininosuccinate synthase 1 (ASS1) expression was significantly decreased and down-regulation of ASS1 was closely correlated with poor prognosis in HCC patients. DNA methylation led to the down-regulation of ASS1 in HCC. Stable silencing of ASS1 promoted migration and invasion of HCC cells, whereas overexpression of ASS1-inhibited metastasis of HCC cells in vivo and in vitro. We also revealed that ASS1-knockdown increased the phosphorylation level of S727STAT3, which contributed to HCC metastasis by up-regulation of inhibitor of differentiation 1 (ID1). These findings indicate that ASS1 inhibits HCC metastasis and may serve as a target for HCC diagnosis and treatment.
Tuponchai P, Kukongviriyapan V, Prawan A, et al.Myricetin ameliorates cytokine-induced migration and invasion of cholangiocarcinoma cells via suppression of STAT3 pathway.
J Cancer Res Ther. 2019 Jan-Mar; 15(1):157-163 [PubMed
] Related Publications
Aim of Study: Cholangiocarcinoma (CCA) is an aggressive cancer with considerable metastatic potential. Various cytokines secreted by tumor cells or cells in the tumor environment can promote the metastasis of CCA. The aim of the present study was to investigate the effect of myricetin on the inhibition of cytokine-induced migration and invasion and the associated cellular mechanisms in human CCA cells.
Materials and Methods: CCA KKU-100 cells were treated with a pro-inflammatory cytokine mixture consisting of interleukin-6, interferon-γ, and tumor necrosis factor-α. The migratory and invasive ability of KKU-100 cells were determined using a wound-healing assay and transwell invasion assay. The effect of myricetin on cytokine-induced STAT3 activation in CCA cells was determined using Western blot analysis. The real-time polymerase chain reaction was performed to determine messenger RNA expression.
Results: Myricetin significantly inhibited cytokine-induced migration and invasion of KKU-100 cells. Detailed molecular analyses revealed that myricetin suppressed the activation of the STAT3 pathway, evidently by a decrease of the active phospho-STAT3 protein expression after myricetin treatment. The cytokine-mediated upregulation of metastasis- and inflammatory-associated genes, which are downstream genes of STAT3 including the intercellular adhesion molecule-1, matrix metalloproteinase-9, inducible nitric oxide synthase, and cyclo-oxygenase 2 (COX-2), were also significantly abolished by myricetin treatment. Moreover, the anti-migratory and anti-invasive activities of a widely prescribed COX inhibitor, indomethacin, were also revealed.
Conclusion: This finding reveals the anti-metastatic effect of myricetin against CCA cells which is mediated partly through suppression of the STAT3 pathway. This compound could be potentially useful as a therapeutic agent against CCA.