Research IndicatorsGraph generated 01 September 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 01 September, 2019 using data from PubMed, MeSH and CancerIndex
Specific Cancers (5)
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: TM4SF1 (cancer-related)
BACKGROUND: Patients with ovarian cancer commonly have a poor prognosis, owing to its invasiveness and distant metastasis. Studies have found TM4SF1 participates in regulating tumor cell invasion and migration. Therefore, it is expected to become a target for anti-invasion and metastasis in ovarian cancer.
METHODS: The expression of TM4SF1 in normal ovarian epithelial tissues, benign ovarian tumor tissues, primary foci of epithelial ovarian cancer and the matched lymph mode metastatic foci was detected using immunohistochemistry to analyze its association with prognosis. The expression of TM4SF1 in HO8910PM, SKOV3 was inhibited using RNAi, and the growth, proliferation, migration, invasion abilities of HO8910PM and SKOV3 cells and the growth of xenograft tumors in nude mice were examined.
RESULTS: (1) The positive expression rate of TM4SF1 protein in epithelial ovarian cancer tissues (90.90%) was higher than that in benign ovarian tumor tissues (65.22%) and normal ovarian epithelial tissues (31.25%), and both differences were significant (P < 0.05). The expression of TM4SF1 protein was positive in all metastatic lymph node foci and matched primary foci (100%). (2) The level of TM4SF1 protein expression was positively correlated with the International Federation of Gynecology and Obstetrics (FIGO) stage and histological grade. However, The positive TM4SF1 protein expression was not an independent factor of prognosis (P > 0.05). (3) Silencing TM4SF1 expression did not affect growth, proliferation, or cell cycle distribution but inhibited the migration and invasion abilities of HO8910PM and SKOV3 cells. Silencing TM4SF1 expression inhibited the growth of xenograft tumors in nude mice.
CONCLUSION: TM4SF1 is a potential target for anti-invasion and metastasis in ovarian cancer.
BACKGROUND: Identification of biomarkers associated with the prognosis of different cancer subtypes is critical to achieve better therapeutic assistance. In colorectal cancer (CRC) the discovery of stable and consistent survival markers remains a challenge due to the high heterogeneity of this class of tumors. In this work, we identified a new set of gene markers for CRC associated to prognosis and risk using a large unified cohort of patients with transcriptomic profiles and survival information.
RESULTS: We built an integrated dataset with 1273 human colorectal samples, which provides a homogeneous robust framework to analyse genome-wide expression and survival data. Using this dataset we identified two sets of genes that are candidate prognostic markers for CRC in stages III and IV, showing either up-regulation correlated with poor prognosis or up-regulation correlated with good prognosis. The top 10 up-regulated genes found as survival markers of poor prognosis (i.e. low survival) were: DCBLD2, PTPN14, LAMP5, TM4SF1, NPR3, LEMD1, LCA5, CSGALNACT2, SLC2A3 and GADD45B. The stability and robustness of the gene survival markers was assessed by cross-validation, and the best-ranked genes were also validated with two external independent cohorts: one of microarrays with 482 samples; another of RNA-seq with 269 samples. Up-regulation of the top genes was also proved in a comparison with normal colorectal tissue samples. Finally, the set of top 100 genes that showed overexpression correlated with low survival was used to build a CRC risk predictor applying a multivariate Cox proportional hazards regression analysis. This risk predictor yielded an optimal separation of the individual patients of the cohort according to their survival, with a p-value of 8.25e-14 and Hazard Ratio 2.14 (95% CI: 1.75-2.61).
CONCLUSIONS: The results presented in this work provide a solid rationale for the prognostic utility of a new set of genes in CRC, demonstrating their potential to predict colorectal tumor progression and evolution towards poor survival stages. Our study does not provide a fixed gene signature for prognosis and risk prediction, but instead proposes a robust set of genes ranked according to their predictive power that can be selected for additional tests with other CRC clinical cohorts.
Activation of programmed cell death 1 (PD‑1)/PD‑ligand 1 (PD‑L1) can promote immune suppression of the tumor microenvironment. However, the effects and mechanisms of PD‑L1 silencing on colorectal cancer growth are largely unknown. In the present study, PD‑L1 expression was compared in colorectal cancer and paracancerous tissues by immunofluorescence. A stable colorectal carcinoma cell line encoding PD‑L1 short hairpin RNA (shRNA) was established. Thereafter, inoculated tumors were modeled in C57B/L6 mice. Experiments were divided into 3 groups: control group, vector group, and PD‑L1 silencing group (inoculated with the stable CT26 cell line encoding PD‑L1 shRNA). Following decapitation of the mice, tumors were weighed and apoptosis of tumor cells was detected. The number and viability of cluster of differentiation (CD)4+ and CD8+ T cells were analyzed by flow cytometry and a cell counting kit assay, respectively. Compared with paracancerous tissue, colorectal cancer tissue extensively expressed PD‑L1, RAC‑α serine/threonine‑protein kinase (AKT), and phosphatidylinositol 3‑kinase (PI3K). Lymphocyte‑activating gene 3 (LAG‑3) expression was observed at the edge of tumor tissue, but rarely observed in paracancerous tissue. A stable CT26 cell line encoding PD‑L1 shRNA was established, and lack of PD‑L1 expression was confirmed by reverse transcription‑polymerase chain reaction and western blotting. Compared with the control, the shPD‑L1 group demonstrated reduced tumor growth, a high level of apoptosis in tumor cells, a low level of PI3K and AKT expression, and an increased number of cells and greater activity of CD4+ T and CD8+ T cells. Taken together, PD‑L1 silencing promoted tumor cell apoptosis, at least in part, through the activation of CD4+ and CD8+ T cells.
MiRNA (miR)-206 plays a tumor suppressor role in various cancer types. Here, we investigated whether miR-206 is involved in prostaglandin E2 (PGE2)-induced epithelial-mesenchymal transition (EMT) in colorectal cancer (CRC) cells through the targetting of transmembrane 4 L six family member 1 (TM4SF1).The effect of PGE2 on growth and apoptosis of CRC cells was evaluated using the MTT assay and flow cytometry analysis, respectively. TM4SF1 and miR-206 expression levels were determined with quantitative polymerase chain reaction (qRT-PCR) in CRC tissues and cell lines. The concentration of PGE2 in the serum of CRC patients and healthy controls was measured with an ELISA kit. A miR-206 or TM4SF1 construct was transfected into cells with PGE2. Transwell migration and invasion assays were used to examine cell migration and invasion properties. Additionally, a luciferase assay was performed to determine whether TM4SF1 was directly targetted by miR-206.We found that miR-206 was down-regulated and TM4SF1 was up-regulated in human CRC tissues and cell lines. Moreover, miR-206 was negatively correlated with TM4SF1 expression. Bioinformatics analysis and a luciferase reporter assay revealed that miR-206 directly targetted the 3'-untranslated region (UTR) of TM4SF1, and TM4SF1 expression was reduced by miR-206 overexpression at both the mRNA and protein levels. Additionally, PGE2 significantly suppressed the expression of miR-206 and increased the expression of TM4SF1 in CRC cells. PGE2 induction led to enhanced CRC cell proliferation, migration, and invasion. Moreover, the overexpression of miR-206 decreased CRC cell proliferation, migration, and invasion compared with control group in PGE2-induced cells, and these effects could be recovered by the overexpression of TM4SF1. Overexpression of miR-206 also suppressed the expression of β-catenin, VEGF, MMP-9, Snail, and Vimentin and enhanced E-cadherin expression in PGE2-induced cells. These results could be reversed by the overexpression of TM4SF1. At last, up-regulation of miR-206 suppressed expression of
microRNAs (miRNAs) regulate gene expression post-transcriptionally and have been extensively tested as therapeutic molecules against several human diseases.
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related death in the world with a five-year survival rate of less than 5%. Not all PDAC are the same, because there exist intra-tumoral heterogeneity between PDAC, which poses a great challenge to personalized treatments for PDAC.
METHODS: To dissect the molecular heterogeneity of PDAC, we performed a retrospective meta-analysis on whole transcriptome data from more than 1200 PDAC patients. Subtypes were identified based on non-negative matrix factorization (NMF) biclustering method. We used the gene set enrichment analysis (GSEA) and survival analysis to conduct the molecular and clinical characterization of the identified subtypes, respectively.
RESULTS: Six molecular and clinical distinct subtypes of PDAC: L1-L6, are identified and grouped into tumor-specific (L1, L2 and L6) and stroma-specific subtypes (L3, L4 and L5). For tumor-specific subtypes, L1 (~ 22%) has enriched carbohydrate metabolism-related gene sets and has intermediate survival. L2 (~ 22%) has the worst clinical outcomes, and is enriched for cell proliferation-related gene sets. About 23% patients can be classified into L6, which leads to intermediate survival and is enriched for lipid and protein metabolism-related gene sets. Stroma-specific subtypes may contain high non-epithelial contents such as collagen, immune and islet cells, respectively. For instance, L3 (~ 12%) has poor survival and is enriched for collagen-associated gene sets. L4 (~ 14%) is enriched for various immune-related gene sets and has relatively good survival. And L5 (~ 7%) has good clinical outcomes and is enriched for neurotransmitter and insulin secretion related gene sets. In the meantime, we identified 160 subtype-specific markers and built a deep learning-based classifier for PDAC. We also applied our classification system on validation datasets and observed much similar molecular and clinical characteristics between subtypes.
CONCLUSIONS: Our study is the largest cohort of PDAC gene expression profiles investigated so far, which greatly increased the statistical power and provided more robust results. We identified six molecular and clinical distinct subtypes to describe a more complete picture of the PDAC heterogeneity. The 160 subtype-specific markers and a deep learning based classification system may be used to better stratify PDAC patients for personalized treatments.
Du X, Fan W, Chen YmicroRNA-520f inhibits hepatocellular carcinoma cell proliferation and invasion by targeting TM4SF1.
Gene. 2018; 657:30-38 [PubMed
] Related Publications
microRNAs (miRNAs) are reported to play crucial roles in tumorigenesis. Dysregulation of miR-520f has been implicated to be involved in several cancer progressions. However, the biological functions of miR520f in hepatocellular carcinoma (HCC) remain unclear. Thus, the molecular mechanism underlying miR-520f on HCC development was investigated in this study. Here, we found that miR-520f was remarkably down-regulated in human HCC samples and cell lines compared to paired normal tissues and cell lines as detected by qRT-PCR. Furthermore, the deregulated miR-520f was strongly associated with larger tumor size, advanced TNM stage, and metastasis in HCC patients. Functional investigations revealed that overexpression of miR-520f significantly suppressed cell proliferation, invasion and migration, caused cell cycle arrested at G0/G1 phase, and promoted cell apoptosis in HCC cells according to MTT, colony formation, transwell, and flow cytometry assays, respectively, whereas, downregulation of miR-520f exhibited inverse effects. Transmembrane-4 L-Six family member-1 (TM4SF1) was identified as a direct target of miR-520f, and an inverse relationship was found between miR-520f and TM4SF1 mRNA levels in HCC specimens. Rescue experiments suggested that restoration of TM4SF1 partially abolished miR-520f-meidated cell proliferation and invasion inhibition in HCC cells through regulating P13K/AKT and p38 MAPK signaling pathways. In conclusion, these data indicated that miR-520f acted as tumor suppressor in HCC proliferation and invasion by targeting TM4SF1, which might provide potential therapeutic evidence for HCC patients.
Hayashi M, Futawaka K, Matsushita M, et al.GH directly stimulates UCP3 expression.
Growth Horm IGF Res. 2018; 40:44-54 [PubMed
] Related Publications
OBJECTIVE: We evaluated the direct action of GH signaling in energy homeostasis in myocytes.
DESIGN: We investigated the GH-induced expression of UCP3 in human embryonic kidney 293 cells, human H-EMC-SS chondrosarcoma cells, murine C2C12 skeletal muscle myoblasts, and rat L6 skeletal muscle cells, as well as its direct effect on the GHR/JAK/STAT5 pathway using a combination of a reporter assay, real-time quantitative polymerase chain reaction, and western blotting.
RESULTS: We demonstrated that the regulation of energy metabolism by GH involves UCP3 via activated STAT5, a signal transducer downstream of GH. UCP3 expression increased with STAT5 in a dose-dependent manner and was higher than that of UCP2. We confirmed the functional STAT5 binding site consensus sequences at -861 and -507 bp in the UCP3 promoter region.
CONCLUSION: The results suggest that GH stimulates UCP3 directly and that UCP2 and that UCP3 participate in the signal transduction pathway that functions downstream of the GHR/JAK/STAT.
Transmembrane 4 L6 family member 1 (TM4SF1) belongs to the 4-transmembrane-domain family and functions as an oncogene in multiple human cancers. In this work, we aim to determine TM4SF1 expression and its prognostic impact on patients with invasive breast cancer.Overall, we enrolled 209 invasive breast cancer patients and immunohistochemically examined the expression of TM4SF1 in tumor specimens. The relationship between TM4SF1 expression and clinicopathological parameter and patient survival of breast cancer patients was analyzed.Among the 209 cases, 137 (65.6%) exhibited high expression of TM4SF1. High TM4SF1 expression was significantly associated with advanced histological grade and negative estrogen receptor and progesterone receptor status. Triple-negative breast cancer (TNBC) tumors were more likely to express high levels of TM4SF1 than non-TNBC cases. Patients with high tumoral expression of TM4SF1 had a significantly shorter disease-free survival (DFS; P = .00) and overall survival (OS; P = .01) than those with low expression of TM4SF1. When survival analysis was restricted to the 167 patients (79.9%) receiving adjuvant chemotherapy, TM4SF1 expression was also correlated with poorer DFS and OS (P = .00). In multiple Cox regression analysis TM4SF1 expression remained an independent prognostic indicator for OS and DFS.TM4SF1 is upregulated and serves as an independent poor prognostic indicator in invasive breast cancer.
BACKGROUND: Neuroblastoma is a paediatric cancer that despite multimodal therapy still has a poor outcome for many patients with high risk tumours. Retinoic acid (RA) promotes differentiation of some neuroblastoma tumours and cell lines, and is successfully used clinically, supporting the view that differentiation therapy is a promising strategy for treatment of neuroblastoma. To improve treatment of a wider range of tumour types, development and testing of novel differentiation agents is essential. New pre-clinical models are therefore required to test therapies in a rapid cost effective way in order to identify the most useful agents.
METHODS: As a proof of principle, differentiation upon ATRA treatment of two MYCN-amplified neuroblastoma cell lines, IMR32 and BE2C, was measured both in cell cultures and in tumours formed on the chick chorioallantoic membrane (CAM). Differentiation was assessed by 1) change in cell morphology, 2) reduction in cell proliferation using Ki67 staining and 3) changes in differentiation markers (STMN4 and ROBO2) and stem cell marker (KLF4). Results were compared to MLN8237, a classical Aurora Kinase A inhibitor. For the in vivo experiments, cells were implanted on the CAM at embryonic day 7 (E7), ATRA treatment was between E11 and E13 and tumours were analysed at E14.
RESULTS: Treatment of IMR32 and BE2C cells in vitro with 10 μM ATRA resulted in a change in cell morphology, a 65% decrease in cell proliferation, upregulation of STMN4 and ROBO2 and downregulation of KLF4. ATRA proved more effective than MLN8237 in these assays. In vivo, 100 μM ATRA repetitive treatment at E11, E12 and E13 promoted a change in expression of differentiation markers and reduced proliferation by 43% (p < 0.05). 40 μM ATRA treatment at E11 and E13 reduced proliferation by 37% (p < 0.05) and also changed cell morphology within the tumour.
CONCLUSION: Differentiation of neuroblastoma tumours formed on the chick CAM can be analysed by changes in cell morphology, proliferation and gene expression. The well-described effects of ATRA on neuroblastoma differentiation were recapitulated within 3 days in the chick embryo model, which therefore offers a rapid, cost effective model compliant with the 3Rs to select promising drugs for further preclinical analysis.
Cao R, Wang G, Qian K, et al.TM4SF1 regulates apoptosis, cell cycle and ROS metabolism via the PPARγ-SIRT1 feedback loop in human bladder cancer cells.
Cancer Lett. 2018; 414:278-293 [PubMed
] Related Publications
Transmembrane-4-L-Six-Family-1 (TM4SF1) is a member of the L6 family and functions as a signal transducer to regulate cell development, growth and motility. Here we show that TM4SF1 is strongly upregulated in human muscle invasive bladder cancer (MIBC) tissues, corroborating the bioinformatical results of transcriptome analysis. Moreover, tissue microarray (TMA) shows significant correlations (p < 0.05) between high expression of TM4SF1 and T stage, TNM stage, lymph node metastasis status and survival rate of MIBC patients, indicating a positive association between TM4SF1 expression and poorer prognosis. Furthermore, in vitro and in vivo studies indicate that the proliferation of human bladder cancer (BCa) cells is significantly suppressed by knockdown of TM4SF1 (p < 0.05). Functionally, the reduction of TM4SF1 could induce cell cycle arrest and apoptosis possibly via the upregulation of reactive oxygen species (ROS) in BCa cells. In addition, these observations could be recovered by treatment with GW9662 (antagonist of PPARγ) and resveratrol (activator of SIRT1). Taken together, our results suggest that high expression of TM4SF1 predicts poor prognosis of MIBC.
The association of ribosomal proteins with carcinogenesis of nasopharyngeal carcinoma (NPC) has been established in a limited subset of ribosomal protein genes. To date, three ribosomal protein genes,
Park YR, Kim SL, Lee MR, et al.MicroRNA-30a-5p (miR-30a) regulates cell motility and EMT by directly targeting oncogenic TM4SF1 in colorectal cancer.
J Cancer Res Clin Oncol. 2017; 143(10):1915-1927 [PubMed
] Related Publications
PURPOSE: Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide, and many oncogenes and tumor suppressor genes are involved in CRC. MicroRNAs (miRNAs) are small non-coding RNAs that can negatively regulate gene expression. Previous studies have revealed that miRNAs regulate the development and progression of many cancers. In this study, we investigated the role of microRNA-30a-5p (miR-30a) in CRC and its unknown mechanisms.
METHODS: qRT-PCR was used to detect miR-30a and TM4SF1 mRNA expression in CRC specimens and cell lines. CRC cell migration and invasion were assessed after transfection with miR-30a or TM4SF1 using wound healing and trans-well migration and invasion assays. Transmembrane-4-L-six-family protein (TM4SF1) was validated as a target of miR-30a in CRC through luciferase reporter assay and bioinformatics algorithms. Moreover, two EMT regulators, E-cadherin and VEGF, were also identified using Western blotting and immunohistochemistry.
RESULTS: We found that miR-30a was down-regulated in CRC tumor tissues and cell lines, and miR-30a was inversely associated with advanced stage and lymph node metastatic status compared with normal tissues. miR-30a decreased migration and invasion in CRC cell lines, and miR-30a overexpression not only down-regulated TM4SF1 mRNA and protein expression, but also inhibited the expression of VEGF and enhanced expression of E-cadherin. We also showed that TM4SF1 was up-regulated in CRC tumor specimens compared with adjacent normal tissues, and TM4SF1 expression was significantly associated with advanced stage and lymph node status compared with adjacent normal tissues.
CONCLUSIONS: These results suggest that miR-30a is an important regulator of TM4SF1, VEGF, and E-cadherin for CRC lymph node metastasis, a potential new therapeutic target in CRC.
Transmembrane-4-L-six-family-1(TM4SF1), a four-transmembrane L6 family member, is highly expressed in various pancreatic cancer cell lines and promotes cancer cells metastasis. However, the TM4SF1-associated signaling network in metastasis remains unknown. In the present study, we found that TM4SF1 affected the formation and function of invadopodia. Silencing of TM4SF1 reduced the expression of DDR1 significantly in PANC-1 and AsPC-1 cells. Through double fluorescence immuno-staining and Co-immunoprecipitation, we also found that TM4SF1 colocalized with DDR1 and had an interaction with DDR1. In addition, upregulating the expression of DDR1 rescued the inhibitory effects of cell migration and invasion, the expression of MMP2 and MMP9 and the formation and function of invadopodia when TM4SF1 silenced. In pancreatic cancer tissues, qRT-PCR and scatter plots analysis further determined that TM4SF1 had a correlation with DDR1. Collectively, our study provides a novel regulatory pathway involving TM4SF1, DDR1, MMP2 and MMP9, which promotes the formation and function of invadopodia to support cell migration and invasion in pancreatic cancer.
Cancer stem-like cells have been identified in primary human tumors and cancer cell lines. Previously we found TM4SF1 gene was highly expressed in side population (SP) cells from esophageal squamous cell carcinoma (ESCC) cell lines, but the role and underlying mechanism of TM4SF1 in ESCC remain unclear. In this study, we observed TM4SF1 was up-regulated but miR-141 was down-regulated in SP cells isolated from ESCC cell lines. TM4SF1 could stimulate the self-renewal ability and carcinogenicity of esophageal cancer stem-like cells, and promote cell invasion and migration. In miR-141 overexpression cells, the expression of TM4SF1 was significantly reduced. We also found that overexpression of miR-141 could abolish the self-renewal ability and carcinogenicity of esophageal cancer stem-like cells and decrease cell invasion and migration by suppressing TM4SF1. Consequently, TM4SF1 is a direct target gene of miR-141. The regulation of TM4SF1 by miR-141 may play an important role in controlling self-renewals of esophageal cancer stem-like cells. It may also promote the development of new therapeutic strategies and efficient drugs to target ESCC stem-like cells.
Cao J, Yang JC, Ramachandran V, et al.TM4SF1 Regulates Pancreatic Cancer Migration and Invasion In Vitro and In Vivo.
Cell Physiol Biochem. 2016; 39(2):740-50 [PubMed
] Related Publications
BACKGROUND/AIMS: The cell surface protein transmembrane 4 L6 family member 1 (TM4SF1) has been detected in various tumors and plays a major role in the development of cancer. We aimed to investigate the effects of TM4SF1 on the migration and invasion of pancreatic cancer in vitro and in vivo and explore its related molecular mechanisms.
METHODS: qRT-PCR and immunohistochemical analyses were used to measure the expression of TM4SF1 in pancreatic cancer tissues and adjacent tissues. TM4SF1 was silenced using siRNA and shRNA to investigate the role of this protein in the proliferation and metastasis of pancreatic cancer cells. MTS and Transwell assays were used to examine the effect of TM4SF1 on pancreatic cancer cell lines. The expression and activity of MMP-2 and MMP-9 were determined by qRT-PCR, western blots and gelatin zymography. In vivo, orthotopic pancreatic tumor models were used to examine the formation of metastasis.
RESULTS: qRT-PCR and immunohistochemical analyses showed that TM4SF1 was highly expressed in pancreatic cancer tissues compared with the adjacent tissues. In in vitro experiments the silencing of TM4SF1 reduced cell migration and invasion and down-regulated the expression and activity of MMP-2 and MMP-9. However, no significant difference in cell proliferation was detected after silencing TM4SF1. Additionally, knocking down TM4SF1 decreased the formation of lung and liver metastases in orthotopic pancreatic tumor models.
CONCLUSION: Our results demonstrate that the expression of TM4SF1 is higher in pancreatic cancer tissues and pancreatic cancer cell lines than controls. Knockdown of TM4SF1 inhibited the migration and invasion of pancreatic cancer cells by regulating the expression and activity of MMP-2 and MMP-9, which suggests that TM4SF1 may play a significant role in metastasis in pancreatic cancer.
Futawaka K, Tagami T, Fukuda Y, et al.Growth hormone regulates the expression of UCP2 in myocytes.
Growth Horm IGF Res. 2016; 29:57-62 [PubMed
] Related Publications
OBJECTIVE: To determine if and how growth hormone (GH) signaling is involved in energy metabolism.
DESIGN: We used human embryonic kidney TSA201 cells, human H-EMC-SS chondrosarcoma cells, rat L6 skeletal muscle cells, and murine C2C12 skeletal muscle myoblasts to investigate GH-induced expression of uncoupling protein2 (UCP2) to the GHR/JAK/STAT5 pathway by a combination of a reporter assay, electrophoretic mobility shift assay (EMSA), real-time quantitative PCR, Western blotting.
RESULTS: We demonstrated that the regulation energy metabolism, which was hypothesized to be directly acted on by GH, involves UCP2 via activated STAT5B, a signal transducer downstream of GH. We also showed that the sequence at the -586 'TTCnGA' may function as a novel putative consensus sequence of STAT5s.
CONCLUSION: The results suggest that GH regulates energy metabolism directly in myocytes and that UCP2 participates in the signal transduction pathway that functions downstream of the GHR/JAK/STAT.
Ma Y, Zhou W, Hong L, Wu ZEstablishment of a Novel Monoclonal Antibody L6 Specific to NOB1.
Monoclon Antib Immunodiagn Immunother. 2016; 35(2):100-3 [PubMed
] Related Publications
NOB1, a transcription-associated protein, may play important roles in the development of many cancers. In this study, we have efficiently generated one monoclonal antibody (MAb) against NOB1. Enzyme-linked immunosorbent assay (ELISA) and western blot were used to screen the hybridomas. As a result, one MAb named L6 (IgG1) effective in detecting the recombinant and the cellular NOB1 protein was characterized. Using L6, NOB1 was found to be upregulated in gastric cancer cells and tissues compared with normal gastric epithelial cells and nonneoplastic tissues. The expression of NOB1 was also found to be higher in multidrug-resistant gastric cancer cells than that of sensitive cells. This novel MAb will be valuable for investigating the role of NOB1 in carcinogenesis and multidrug resistance of gastric cancer.
Fajardo AM, MacKenzie DA, Olguin SL, et al.Antioxidants Abrogate Alpha-Tocopherylquinone-Mediated Down-Regulation of the Androgen Receptor in Androgen-Responsive Prostate Cancer Cells.
PLoS One. 2016; 11(3):e0151525 [PubMed
] Free Access to Full Article Related Publications
Tocopherylquinone (TQ), the oxidation product of alpha-tocopherol (AT), is a bioactive molecule with distinct properties from AT. In this study, AT and TQ are investigated for their comparative effects on growth and androgenic activity in prostate cancer cells. TQ potently inhibited the growth of androgen-responsive prostate cancer cell lines (e.g., LAPC4 and LNCaP cells), whereas the growth of androgen-independent prostate cancer cells (e.g., DU145 cells) was not affected by TQ. Due to the growth inhibitory effects induced by TQ on androgen-responsive cells, the anti-androgenic properties of TQ were examined. TQ inhibited the androgen-induced activation of an androgen-responsive reporter and inhibited the release of prostate specific antigen from LNCaP cells. TQ pretreatment was also found to inhibit AR activation as measured using the Multifunctional Androgen Receptor Screening assay. Furthermore, TQ decreased androgen-responsive gene expression, including TM4SF1, KLK2, and PSA over 5-fold, whereas AT did not affect the expression of androgen-responsive genes. Of importance, the antiandrogenic effects of TQ on prostate cancer cells were found to result from androgen receptor protein down-regulation produced by TQ that was not observed with AT treatment. Moreover, none of the androgenic endpoints assessed were affected by AT. The down-regulation of androgen receptor protein by TQ was abrogated by co-treatment with antioxidants. Overall, the biological actions of TQ were found to be distinct from AT, where TQ was found to be a potent inhibitor of cell growth and androgenic activity in androgen-responsive prostate cancer cells.
Park YR, Lee ST, Kim SL, et al.MicroRNA-9 suppresses cell migration and invasion through downregulation of TM4SF1 in colorectal cancer.
Int J Oncol. 2016; 48(5):2135-43 [PubMed
] Related Publications
Transmembrane-4-L6 family 1 (TM4SF1) is upregulated in colorectal carcinoma (CRC). However, the mechanism leading to inhibition of the TM4SF1 is not known. In the present study, we investigated the regulation of TM4SF1 and function of microRNAs (miRNAs) in CRC invasion and metastasis. We analyzed 60 colon cancers and paired normal specimens for TM4SF1 and miRNA-9 (miR-9) expression using quantitative real-time PCR. A bioinformatics analysis identified a putative miR-9 binding site within the 3'-UTR of TM4SF1. We also found that TM4SF1 was upregulated in CRC tissues and CRC cell lines. The expression of TM4SF1 was positively correlated with clinical advanced stage and lymph node metastasis. Moreover, a luciferase assay revealed that miR-9 directly targeted 3'-UTR-TM4SF1. Overexpression of miR-9 inhibited expression of TM4SF1 mRNA and protein, wound healing, transwell migration and invasion of SW480 cells, whereas, overexpression of anti-miR-9 and siRNA-TM4SF1 inversely regulated the TM4SF1 mRNA and protein level in HCT116 cells. Furthermore, miR-9 suppressed not only TM4SF1 expression but also MMP-2, MMP-9 and VEGF expression. In clinical specimens, miR-9 was generally down-regulated in CRC and inversely correlated with TM4SF1 expression. These results suggest that miR-9 functions as a tumor-suppressor in CRC, and that its suppressive effects mediate invasion and metastasis by inhibition of TM4SF1 expression. Our results also indicate that miR-9 might be a novel target for the treatment of CRC invasion and metastasis.
Cancer cells contain a small population of cancer stem cells or cancer initiating cells, which can be enriched in the side population (SP) after fluorescence activated cell sorting. To examine the members of the ADAM, ADAMTS and MMP gene families related to phenotypes of the SP and the main population (MP), we screened the expression of all the members in the propagated SP and MP of A549 lung adenocarcinoma cells, and found that the relative expression ratio of ADAM23 in the MP to the SP is most highly increased, but none of them are increased in the SP. A similar result on the ADAM23 expression was obtained with another cell line, Calu-3 cells. Overexpression of ADAM23 inhibited colony formation, cell adhesion and migration, and knockdown of ADAM23 by shRNA showed the reverse effects. ADAM23-mediated suppression of colony formation, cell adhesion and migration was greatly reduced by treatment with neutralizing anti-ADAM23 antibody, anti-αvβ3 integrin antibody and/or ADAM23 disintegrin peptide. Expression of cancer stem cell-related genes, including AKRC1/2, TM4SF1 and NR0B1, was increased by knockdown of ADAM23. In addition, lung metastasis of A549 transfectants with different levels of ADAM23 expression was negatively regulated by the ADAM23 expression levels. Our data provide evidence that ADAM23 plays a role in suppression of cancer cell progression through interaction with αvβ3 integrin, and suggest that downregulation of ADAM23 in SP cells may contribute toward providing a cancer stem cell phenotype by facilitating the activity of integrin αvβ3.
BACKGROUND: TM4SF1 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and affects the development of this cancer. Also, multidrug resistance (MDR) is generally associated with tumor chemoresistance in pancreatic cancer. However, the correlation between TM4SF1 and MDR remains unknown. This research aims to investigate the effect of TM4SF1 on gemcitabine resistance in PDAC and explore the possible molecular mechanism between TM4SF1 and MDR.
METHODS: The expression of TM4SF1 was evaluated in pancreatic cancer cell lines and human pancreatic duct epithelial (HPDE) cell lines by quantitative RT-PCR. TM4SF1 siRNA transfection was carried out using Hiperfect transfection reagent to knock down TM4SF1. The transcripts were analyzed by quantitative RT-PCR, RT-PCR and western blotting for further study. The cell proliferation and apoptosis were obtained to investigate the sensitivity to gemcitabine of pancreatic cancer cells after silencing TM4SF1 in vitro. We demonstrated that cell signaling of TM4SF1 mediated chemoresistance in cancer cells by assessing the expression of multidrug resistance (MDR) genes using quantitative RT-PCR. In vivo, we used orthotopic pancreatic tumor models to investigate the effect of proliferation after silencing TM4SF1 by a lentivirus-mediated shRNA in MIA PaCa-2 cell lines.
RESULTS: The mRNA expression of TM4SF1 was higher in seven pancreatic cancer cell lines than in HPDE cell lines. In three gemcitabine-sensitive cell lines (L3.6pl, BxPC-3, SU86.86), the expression of TM4SF1 was lower than that in four gemcitabine-resistant cell lines (MIA PaCa-2, PANC-1, Hs766T, AsPC-1). We evaluated that TM4SF1 was a putative target for gemcitabine resistance in pancreatic cancer cells. Using AsPC-1, MIA PaCa-2 and PANC-1, we investigated that TM4SF1 silencing affected cell proliferation and increased the percentages of cell apoptosis mediated by treatment with gemcitabine compared with cells which were treated with negative control. This resistance was associated with the expression of multidrug resistance genes including ABCB1 and ABCC1. In vivo, silencing of TM4SF1 in MIA PaCa-2 cell lines increased the effectiveness of gemcitabine-based treatment in orthotopic pancreatic tumor models evaluated using noninvasive bioluminescent imaging.
CONCLUSION: These findings suggest that TM4SF1 is a surface membrane antigen that is highly expressed in pancreatic cancer cells and increases the chemoresistance to gemcitabine. Thus, TM4SF1 may be a promising target to overcome the chemoresistance of pancreatic cancer.
Boonmuen N, Gong P, Ali Z, et al.Licorice root components in dietary supplements are selective estrogen receptor modulators with a spectrum of estrogenic and anti-estrogenic activities.
Steroids. 2016; 105:42-9 [PubMed
] Free Access to Full Article Related Publications
Licorice root extracts are often consumed as botanical dietary supplements by menopausal women as a natural alternative to pharmaceutical hormone replacement therapy. In addition to their components liquiritigenin (Liq) and isoliquiritigenin (Iso-Liq), known to have estrogenic activity, licorice root extracts also contain a number of other flavonoids, isoflavonoids, and chalcones. We have investigated the estrogenic activity of 7 of these components, obtained from an extract of Glycyrrhiza glabra powder, namely Glabridin (L1), Calycosin (L2), Methoxychalcone (L3), Vestitol (L4), Glyasperin C (L5), Glycycoumarin (L6), and Glicoricone (L7), and compared them with Liq, Iso-Liq, and estradiol (E2). All components, including Liq and Iso-Liq, have low binding affinity for estrogen receptors (ERs). Their potency and efficacy in stimulating the expression of estrogen-regulated genes reveal that Liq and Iso-Liq and L2, L3, L4, and L6 are estrogen agonists. Interestingly, L3 and L4 have an efficacy nearly equivalent to E2 but with a potency ca. 10,000-fold less. The other components, L1, L5 and L7, acted as partial estrogen antagonists. All agonist activities were reversed by the antiestrogen, ICI 182,780, or by knockdown of ERα with siRNA, indicating that they are ER dependent. In HepG2 hepatoma cells stably expressing ERα, only Liq, Iso-Liq, and L3 stimulated estrogen-regulated gene expression, and in all cases gene stimulation did not occur in HepG2 cells lacking ERα. Collectively, these findings classify the components of licorice root extracts as low potency, mixed ER agonists and antagonists, having a character akin to that of selective estrogen receptor modulators or SERMs.
McNamara KL, Aronson MD, Cohen ZIs there a role for prophylactic colectomy in Lynch syndrome patients with inflammatory bowel disease?
Int J Colorectal Dis. 2016; 31(1):9-13 [PubMed
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PURPOSE: Lynch syndrome and chronic inflammatory bowel disease are two important risk factors for colorectal cancer. It is unclear whether Lynch syndrome patients with inflammatory bowel disease are at sufficiently increased risk for colorectal cancer to warrant prophylactic colectomy. This study aims to identify all cases of Lynch syndrome and concurrent inflammatory bowel disease in a large familial gastrointestinal cancer registry, define incidence of colorectal cancer, and characterize mismatch repair protein gene mutation status and inflammatory bowel disease-associated colorectal cancer risk factors.
METHODS: We retrospectively identified and collected clinical data for all cases with confirmed diagnoses of Lynch syndrome and inflammatory bowel disease in the Familial Gastrointestinal Cancer Registry at Mount Sinai Hospital in Toronto, Canada.
RESULTS: Twelve cases of confirmed Lynch syndrome, and concurrent inflammatory bowel disease were identified. Four cases developed colorectal cancer. An additional five cases had colectomy; one was performed for severe colitis, and four were performed for low-grade dysplasia. None of these surgical specimens contained malignancy or high-grade dysplasia.
CONCLUSIONS: The presentation of Lynch syndrome with inflammatory bowel disease is uncommon and not well described in the literature. This small but important series of twelve cases is the largest reported to date. In this series, patients with Lynch syndrome and concurrent inflammatory bowel disease do not appear to have sufficiently increased risk for colorectal cancer to recommend prophylactic surgery. Therefore, the decision to surgery should continue to be guided by surgical indications for each disease. Further evaluation of this important area will require multi-institutional input.
McFall T, Patki M, Rosati R, Ratnam MRole of the short isoform of the progesterone receptor in breast cancer cell invasiveness at estrogen and progesterone levels in the pre- and post-menopausal ranges.
Oncotarget. 2015; 6(32):33146-64 [PubMed
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Overexpression of the progesterone receptor (PR) isoform A (PR-A) is a negative prognosticator for estrogen receptor (ER)-positive breast cancer but in vitro studies have implicated PR-B in progestin-induced invasiveness. As estrogen is known to suppress invasiveness and tumor progression and as the in vitro studies were conducted in models that either lacked ER or excluded estrogen, we examined the role of PR isoforms in the context of estrogen signaling. Estrogen (< 0.01nM) strongly suppressed invasiveness in various ER+ model cell lines. At low (< 1nM) concentrations, progestins completely abrogated inhibition of invasiveness by estrogen. It was only in a higher (5 nM - 50 nM) concentration range that progestins induced invasiveness in the absence of estrogen. The ability of low dose progestins to rescue invasiveness from estrogen regulation was exclusively mediated by PR-A, whereas PR-B mediated the estrogen-independent component of progestin-induced invasiveness. Overexpression of PR-A lowered the progestin concentration needed to completely rescue invasiveness. Among estrogen-regulated genes, progestin/PR-A counter-regulated a distinctive subset, including breast tumor progression genes (e.g., HES1, PRKCH, ELF5, TM4SF1), leading to invasiveness. In this manner, at relatively low hormone concentrations (corresponding to follicular stage and post-menopausal breast tissue or plasma levels), progesterone influences breast cancer cell invasiveness by rescuing it from estrogen regulation via PR-A, whereas at higher concentrations the hormone also induces invasiveness independent of estrogen signaling, through PR-B. The findings point to a direct functional link between PR-A and progression of luminal breast cancer in the context of the entire range of pre- and post-menopausal plasma and breast tissue hormone levels.
Pabalan N, Jarjanazi H, Ozcelik HAssociations of the Insertion/Deletion Polymorphism in the ACE Gene and Risk of Gastric Cancer: A Meta-Analysis.
J Gastrointest Cancer. 2015; 46(4):370-9 [PubMed
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BACKGROUND: Reported associations of ACE polymorphisms with gastric cancer have been inconsistent, prompting a meta-analysis of 12 published case-control studies where we estimated risk (odds ratio [OR]).
METHODS: We searched MEDLINE through PubMed and EMBASE for suitable articles that had case-control design with gastric cancer as outcome. In this meta-analysis, our overall findings were subjected to modifier analyses (outlier and sensitivity treatments). We also performed subgroup analysis based on ethnicity (German and Japanese) and histological subtype (intestinal and diffuse).
RESULTS: Significance of the protective effects among homozygote carriers of the II genotype (OR 0.54-0.63, P = 0.01-0.02) disappeared with outlier analysis (OR 0.81-0.88, P = 0.12-0.14). Among DD homozygotes, this treatment altered the direction of association from weak protection (OR 0.95-0.96, P = 0.79-0.82) to increased risk (OR 1.13-1.19, P = 0.14-0.16). No significant associations were observed among ID genotype carriers (OR 0.91-0.94, P = 0.69-0.72). Japanese pooled effects varied across the genotype comparisons (OR 0.93-1.06, P = 0.54-0.72). Sensitivity treatment demonstrated robustness of the II genotype, but not the other two, both in overall and subgroup analyses. Histological subtype analysis yielded protection from intestinal cancer across the comparisons (OR 0.38-0.71, P = 0.15-0.50) but variable results for the diffuse type (OR 0.59-1.32, P = 0.19-0.92).
CONCLUSION: In summary, carriers of the ACE II genotype appear to be protected from gastric cancer, regardless of ethnicity or tumor type.
BACKGROUND: Autophagy is a conserved cellular self-digestion mechanism that can either suppress or promote cancer in a context-dependent manner. In ovarian cancer, prevalent mono-allelic deletion of BECN1 (a canonical autophagy-inducer) suggests that autophagy is impaired to promote carcinogenesis and that Beclin-1 is a haploinsufficient tumor suppressor. Nonetheless, autophagy is known to be readily inducible in ovarian cancer cells. We sought to clarify whether Beclin-1 expression is in fact disrupted in ovarian cancer and whether this impacts autophagy regulation.
METHODS: BECN1 expression levels were assessed using The Cancer Genome Atlas (TCGA) datasets from 398 ovarian high-grade serous cystadenocarcinomas (HGSC) and protein immunoblot data from HGSC samples obtained at our institution. Knockdown of BECN1 and other autophagy-related gene expression was achieved using siRNA in established human ovarian cancer cell lines (CaOV3, OVCAR8, SKOV3, and HeyA8) and a novel early-passage, ascites-derived cell line (iOvCa147-E2). LC3 immunoblot, autophagic flux assays, transmission electron microscopy and fluorescence microscopy were used to assess autophagy.
RESULTS: We observed prevalent mono-allelic BECN1 gene deletion (76%) in TCGA tumors, yet demonstrate for the first time that Beclin-1 protein expression remains relatively unaltered in these and additional samples generated at our institution. Surprisingly, efficient siRNA-mediated Beclin-1 knockdown did not attenuate autophagy induction, whereas knockdown of other autophagy-related genes blocked the process. Beclin-1 knockdown instead decreased cell viability without inducing apoptosis.
CONCLUSIONS: Taken together, these data demonstrate that despite its sustained expression, Beclin-1 is dispensable for autophagy induction in ovarian tumor cells in vitro, yet may be retained to promote cell viability by a mechanism independent of autophagy or apoptosis regulation. Overall, this work makes novel observations about tumor expression of Beclin-1 and challenges the accepted understanding of its role in regulating autophagy in ovarian cancer.
Visintin A, Knowlton K, Tyminski E, et al.Novel Anti-TM4SF1 Antibody-Drug Conjugates with Activity against Tumor Cells and Tumor Vasculature.
Mol Cancer Ther. 2015; 14(8):1868-76 [PubMed
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Antibody-drug conjugates (ADC) represent a promising therapeutic modality for managing cancer. Here, we report a novel humanized ADC that targets the tetraspanin-like protein TM4SF1. TM4SF1 is highly expressed on the plasma membranes of many human cancer cells and also on the endothelial cells lining tumor blood vessels. TM4SF1 is internalized upon interaction with antibodies. We hypothesized that an ADC against TM4SF1 would inhibit cancer growth directly by killing cancer cells and indirectly by attacking the tumor vasculature. We generated a humanized anti-human TM4SF1 monoclonal antibody, v1.10, and armed it with an auristatin cytotoxic agent LP2 (chemical name mc-3377). v1.10-LP2 selectively killed cultured human tumor cell lines and human endothelial cells that express TM4SF1. Acting as a single agent, v1.10-LP2 induced complete regression of several TM4SF1-expressing tumor xenografts in nude mice, including non-small cell lung cancer and pancreas, prostate, and colon cancers. As v1.10 did not react with mouse TM4SF1, it could not target the mouse tumor vasculature. Therefore, we generated a surrogate anti-mouse TM4SF1 antibody, 2A7A, and conjugated it to LP2. At 3 mpk, 2A7A-LP2 regressed several tumor xenografts without noticeable toxicity. Combination therapy with v1.10-LP2 and 2A7A-LP2 together was more effective than either ADC alone. These data provide proof-of-concept that TM4SF1-targeting ADCs have potential as anticancer agents with dual action against tumor cells and the tumor vasculature. Such agents could offer exceptional therapeutic value and warrant further investigation. Mol Cancer Ther; 14(8); 1868-76. ©2015 AACR.
Zheng B, Ohuchida K, Cui L, et al.TM4SF1 as a prognostic marker of pancreatic ductal adenocarcinoma is involved in migration and invasion of cancer cells.
Int J Oncol. 2015; 47(2):490-8 [PubMed
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The cell surface protein Transmembrane 4 L6 family member 1 (TM4SF1) has been detected in various tumors, and its expression on tumor cells is implicated in cancer cell metastasis and patient prognosis. The role of TM4SF1 in malignant tumors remains poorly understood, particularly in pancreatic cancer. We performed immunohistochemical staining to analyze the expression of TM4SF1 in resected pancreatic tissues and investigated the correlation between TM4SF1 expression and prognosis. The function of TM4SF1 in the invasion and migration of pancreatic cancer cells was analyzed in vitro using an RNA interference technique. In pancreatic cancer tissues, TM4SF1 expression was detected in cancer cells, and patients with high tumor levels of TM4SF1 showed longer survival times than those with low TM4SF1 levels (P=0.0332). In vitro, reduced TM4SF1 expression enhanced the migration (P<0.05) and invasion (P<0.05) of pancreatic cancer cells partially via decreased E-cadherin expression. TM4SF1 protein levels were also reduced after TGF-β1-induced epithelial-mesenchymal transition (EMT).TM4SF1 expression is associated with better prognosis in pancreatic cancer. Loss of TM4SF1 contributes to the invasion and migration of pancreatic cancer cells.
Wang P, Bao W, Zhang G, et al.Transmembrane-4-L-six-family-1, a potential predictor for poor prognosis, overexpressed in human glioma.
Neuroreport. 2015; 26(8):455-61 [PubMed
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Transmembrane-4-L-six-family-1 (TM4SF1), a tumor-associated antigen, is expressed in various human epithelial malignancies including breast, ovarian, lung, and colon carcinomas. The aim of the present study was to measure TM4SF1 gene expression in human glioma tissues and to investigate its relationship with patient outcome. We measured TM4SF1 expression in tumor tissue from 72 patients with glioma and in eight control brain tissues by means of quantitative reverse transcription-PCR, western blotting, and immunohistochemistry. The survival data including age, sex, Karnofsky performance scores, epilepsy, size of tumor, extent of resection, pathological grade, and TM4SF1 expression were analyzed using Kaplan-Meier analysis and the multivariate test method (Cox's proportional hazards model). We observed a higher level of TM4SF1 expression in human glioma tissues than in control brain tissues. Furthermore, TM4SF1 expression increased with ascending tumor grade (rs=0.950, P<0.05). Kaplan-Meier analysis with the log-rank test indicated that high TM4SF1 expression had a significant negative impact on overall survival (P<0.001). Moreover, multivariate Cox regression analysis revealed that TM4SF1 was an independent prognostic marker in glioma patients. These findings indicate that (a) TM4SF1 is overexpressed in human gliomas in general and (b) the precise level of expression might predict outcome and could be of clinical value.