The oncogenic role of SOX8 in endometrial carcinoma.
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ABSTRACT:
SUBMITTER: Tian W
PROVIDER: S-EPMC7722791 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundAbhydrolase domain containing 5 (ABHD5) functions as a tumor suppressor in colorectal and prostate cancers. The aim of this study was to investigate the roles of ABHD5 in endometrial cancer.Materials and methodsABHD5 expression was detected in clinical samples by immunohistochemical staining. Cell proliferation and invasion were evaluated with the Cell Counting Kit-8 and Transwell assay, respectively. Western blotting was performed to analyze protein expression. Glucose uptake was assessed by 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose. Lactate production was detected by a lactate assay kit.ResultsIn the present study, ABHD5 was overexpressed in endometrial cancer tissues, and its expression was closely correlated with the International Federation of Gynecology and Obstetrics (FIGO) stage and lymph node metastasis. In addition, we observed that the knockdown of ABHD5 inhibited cell proliferation, invasion, glucose uptake and lactate production in HEC-1A cells, which expressed high levels of ABHD5. Conversely, the opposite effects were observed when ABHD5 was ectopically expressed in Ishikawa cells, which had low levels of ABHD5. Furthermore, the changes in glycolysis regulators (enolase 1 [ENO1], glucose transporter 1 [GLUT1] and lactate dehydrogenase A [LDHA]) and epithelial-to-mesenchymal transition-related proteins (E-cadherin and Snail) in HEC-1A cells with ABHD5 knockdown were consistent with the effects of ABHD5 on glycolysis and cell invasion. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was increased, while the phosphorylated AKT (p-AKT) was decreased when ABHD5 was downregulated. Notably, treatment with the allosteric AKT inhibitor MK-2206 completely abolished the effects caused by ABHD5 overexpression in Ishikawa cells. Finally, ABHD5 knockdown potently suppressed tumor growth in vivo.ConclusionOverall, these results suggest that ABHD5 may play an oncogenic role in endometrial cancer via the AKT pathway.
| S-EPMC6421882 | biostudies-literature
Project description:PurposeEndometrial carcinoma (EC) is a clinically heterogeneous disease characterized by a number of different histological subtypes, and its heterogeneity may be involved in the accumulation of multiple genetic alterations. The aim of this work was to investigate the comprehensive mutational profile of EC tumors, and examine the associations between somatic mutations and clinicopathological features or survival in EC patients.MethodsA total of 100 surgical tumors were obtained from EC patients who had previously undergone surgery. Genomic DNA samples extracted from fresh-frozen tissues were analyzed using the Ion AmpliSeq Cancer Hotspot Panel v2 Kit, covering 50 tumor-related genes.ResultsValidated mutations were detected in 91 of the 100 tumors (91%) and identified in eight of the most frequently mutated genes, namely PTEN (57%), PIK3CA (51%), TP53 (30%), KRAS (23%), CTNNB1 (21%), FBFR2 (13%), FBXW7(10%) and RB1 (9%). PTEN mutations were found to associated with young age (< 60), early-stage, endometrioid histology, non-recurrence and better overall survival (OS). CTNNB1 mutations were associated with young age, endometrioid histology and better OS. On the other hands, TP53 mutations were associated with late-stage, non-endometrioid histology, high-grade, recurrence and worse OS. FBWX7 mutations were associated with late-stage, vascular invasion and lymph node metastasis. FGFR2 mutations correlated with deep (≥ 1/2) myometrial invasion.ConclusionOur comprehensive mutational profile will be useful for understanding and evaluating the molecular characteristics of EC tumors, and may lead to the establishment of novel treatment strategies that improve the survival of patients with EC in the future.
| S-EPMC7810788 | biostudies-literature
Project description:Cytoskeleton-associated protein 2-like (CKAP2L) exerts crucial function in the cell-cycle progression and mitotic spindle formation of neural stem/progenitor cells. However, in hepatocellular carcinoma (HCC), the expression pattern, clinical significance and biologic role of CKAP2L remain unexplored. We analysed The Cancer Genome Atlas (TCGA) database and found that CKAP2L was dramatically upregulated in HCC tissues at the mRNA level compared to adjacent tissues, which was validated in 48 paired HCC and para-tumor tissues using quantitative real-time PCR (qRT-PCR). Immunohistochemical analysis of tissue microarray revealed that CKAP2L was also significantly overexpressed at the protein level. Further clinical and survival analysis of the TCGA cohort revealed that increased CKAP2L expression was strongly associated with reduced overall survival. We further validated that higher CKAP2L protein expression was associated with worse prognosis in the Peking Union Medical College Hospital (PUMCH) cohort. Univariate and multivariate Cox regression analyses in the TCGA and PUMCH cohort suggested that CKAP2L overexpression was an independent risk factor for poor prognosis in HCC patients. Then, we validated that CKAP2L silencing inhibited HCC cell proliferation, migration, and invasion abilities. Knockdown of CKAP2L in Huh7 cells suppressed the growth of xenograft tumors in vivo. Furthermore, qRT-PCR and western blotting results demonstrated that the expression of Class I Phosphoinositide 3-Kinase PIK3CA/p110α and PIK3CB/p110β isoforms reduced obviously in Huh7 cells after depleting CKAP2L. This study demonstrated for the first time that high CKAP2L expression in HCC tissues is significantly correlated with poor prognosis in HCC patients and greatly facilitate the malignancy of HCC, thus providing a new prognostic biomarker and potential therapeutic target.
| S-EPMC7270663 | biostudies-literature
Project description:Hepatitis delta virus (HDV) is a small defective virus that needs hepatitis B virus (HBV) to replicate and propagate. HDV infection affects 20-40 million people worldwide and pegylated interferon (PegIFN) is the only recommended therapy. There is limited data on the contribution of HDV infection to HBV-related liver disease or liver cancer. Evidence from retrospective and cohort studies suggests that HBV/HDV coinfection accelerates progression to cirrhosis and is associated with an increased risk of hepatocellular carcinoma (HCC) development compared to HBV monoinfection. Although the life cycle of HDV is relatively well known, there is only ancillary information on the molecular mechanisms that can drive specific HDV-related oncogenesis. No thorough reports on the specific landscape of mutations or molecular classes of HDV-related HCC have been published. This information could be critical to better understand the uniqueness, if any, of HDV-related HCC and help identify novel targetable mutations. Herein, we review the evidence supporting an oncogenic role of HDV, the main reported mechanisms of HDV involvement and their impact on HCC development.
| S-EPMC7001537 | biostudies-literature
Project description:Aberrant activation of the PI3K/AKT/mTOR pathway is attributed to the pathogenesis of oral squamous cell carcinoma (OSCC). In recent years, increasing evidence suggests the involvement of microRNAs (miRNAs) in oral carcinogenesis by acting as tumor suppressors or oncogenes. TSC1, as a component of the above pathway, regulates several cellular functions such as cell proliferation, apoptosis, migration and invasion. Downregulation of TSC1 is reported in oral as well as several other cancers and is associated with an unfavourable clinical outcome in patients. Here we show that oncogenic miR-130a binds to the 3'UTR of TSC1 and represses its expression. MiR-130a-mediated repression of TSC1 increases cell proliferation, anchorage independent growth and invasion of OSCC cells, which is dependent on the presence of the 3'UTR in TSC1. We observe an inverse correlation between the expression levels of miR-130a and TSC1 in OSCC samples, suggesting that their interaction is physiologically relevant. Delivery of antagomiR-130a to OSCC cells results in a significant decrease in xenograft size. Taken together, the findings of the study indicate that miR-130a-mediated TSC1 downregulation is not only a novel mechanism in OSCC, but also the restoration of TSC1 levels by antagomiR-130a may be a potential therapeutic strategy for the treatment of OSCC.
| S-EPMC8032739 | biostudies-literature
Project description:Clear cell renal cell carcinoma (ccRCC) is the most common adult renal neoplasm and its incidence continues to increase. Collagen is the most abundant extracellular matrix protein in stroma, and contributes to the development and progression of ccRCC. We examined the human collagen type XXIII ?1 chain (COL23A1) expression in ccRCC and the relationship between COL23A1 and patients' survival. We found COL23A1 mRNA was elevated in tumor compared with adjacent normal tissues, which was further validated by TCGA cohort. IHC results from 151 ccRCC cases suggested that high COL23A1 expression correlated with larger tumor size (P?=?0.017) and advanced T stage (P?=?0.011). The overall survival (OS) was shorter for ccRCC patients with high COL23A1 expression (P?=?0.002). In multivariate analysis, high COL23A1 expression was an independent prognostic factor of OS (HR: 3.024, P?=?0.017). Furthermore, COL23A1 knockdown repressed proliferation of ccRCC cell lines by blocking cell cycle progression. Cell adhesion and migration capacity was also downregulated by knockdown of COL23A1. Our data indicate that COL23A1 may be a novel prognostic indicator in ccRCC and might be a specific and accessible biomarker as well as a potential new target for clinical diagnosis of ccRCC.
| S-EPMC5575106 | biostudies-literature
Project description:The aberrant highly expressed T-cell factor 4 (TCF4) has been determined to be closely connected with carcinogenesis of cutaneous squamous cell carcinoma (cSCC) in previous studies. However, the underlying regulatory network and the potential therapeutic targets of TCF4 in SCC are still not fully understood. In this study, the highly expressed TCF4 was observed in human cSCC cancer compared to the paired adjacent tissues. A431 cell lines with TCF4 RNA silencing were found to be the repressive cell proliferation and invasion as well as the enhanced apoptosis. Furthermore, RNA-Seq was conducted and observed that 147 genes were up-regulated (including 113 coding genes and 34 lncRNA) while 172 genes were down-regulated (including 64 coding genes and 108 lncRNA) in TCF4 silencing compared to blank RNAi and untreated control A431 cells. 18 pathways including steroid, porphyrin, arachidonic acid, and retinol metabolism, as well as the functions associated with angiogenesis, inflammatory response, and cell adhesion were involved in the differentially expressed genes of A431 cells with TCF4 silencing. Finally, ChIP-qPCR of TCF4 and β-catenin were performed and we found that the enrichments of β-catenin were lost on the promoters on top ten down-regulated genes in A431 cells with TCF4 silencing compared to the untreated A431. Additionally, in untreated A431 cells, some genes such as ALDH8A1, DRICH1, and UGT1A5 were observed with high enrichment of TCF4, but without β-catenin, which indicated a Wnt/β-catenin independent way of TCF4 for gene transcriptional regulation. In conclusion, we declared that TCF4 played an important role in tumorigenesis of skin cancer via the aberrant activation of variety of signaling pathways, and could be considered as a potential therapeutic target for cSCC treatment.
| S-EPMC6949837 | biostudies-literature
Project description:SND1, a subunit of the miRNA regulatory complex RISC, has been implicated as an oncogene in hepatocellular carcinoma (HCC). In this study, we show that hepatocyte-specific SND1 transgenic mice (Alb/SND1 mice) develop spontaneous HCC with partial penetrance and exhibit more highly aggressive HCC induced by chemical carcinogenesis. Livers from Alb/SND1 mice exhibited a relative increase in inflammatory markers and spheroid-generating tumor-initiating cells (TIC). Mechanistic investigations defined roles for Akt and NF-κB signaling pathways in promoting TIC formation in Alb/SND1 mice. In human xenograft models of subcutaneous or orthotopic HCC, administration of the selective SND1 inhibitor 3', 5'-deoxythymidine bisphosphate (pdTp), inhibited tumor formation without effects on body weight or liver function. Our work establishes an oncogenic role for SND1 in promoting TIC formation and highlights pdTp as a highly selective SND1 inhibitor as a candidate therapeutic lead to treat advanced HCC. Cancer Res; 77(12); 3306-16. ©2017 AACR.
| S-EPMC5488274 | biostudies-literature
Project description:Clear cell renal carcinoma (ccRC) comprises a set of heterogeneous, fast-progressing pathologies with poor prognosis. Analyzing ccRC progression in terms of modifications at the molecular level may provide us with a broader understanding of the disease, paving the way for improved diagnostics and therapeutics. The role of micro-RNAs (miRs) in cancer by targeting both oncogenes and tumor suppressor genes is widely known. Despite this knowledge, the role of specific miRs and their targets in the progression of ccRC is still unknown. To evaluate the action of miRs and their target genes during ccRC progression, here we implemented a three-step method for constructing miR-gene co-expression networks for each progression stage of ccRC as well as for adjacent-normal renal tissue (NT). In the first step, we inferred all miR-gene co-expression interactions for each progression stage of ccRC and for NT. Afterwards, we filtered the whole miR-gene networks by differential gene and miR expression between successive stages: stage I with non-tumor, stage II with stage I, and so on. Finally, all miR-gene interactions whose relationships were inversely proportional (overexpressed miR and underexpressed genes and vice versa) were kept and removed otherwise. We found that miR-217 is differentially expressed in all contrasts; however, its targets were different depending on the ccRC stage. Furthermore, the target genes of miR-217 have a known role in cancer progression-for instance, in stage II network, GALNTL6 is overexpressed, and it is related to cell signaling, survival, and proliferation. In the stage III network, WNK2, a widely known tumor suppressor, is underexpressed. For the stage IV network, IGF2BP2, a post-transcriptional regulator of MYC and PTEN, is overexpressed. This data-driven network approach has allowed us to discover miRs that have different targets through ccRC progression, thus providing a method for searching possible stage-dependent therapeutic targets in this and other types of cancer.
| S-EPMC9354686 | biostudies-literature
Project description:The p70 ribosomal protein S6 kinase 1 (S6K1), a serine/threonine kinase, is commonly overexpressed in a variety of cancers. However, its expression level and functional roles in hepatocellular carcinoma (HCC), which ranks as the third leading cause of cancer-related death worldwide, is still largely unknown. In the current report, we show the in vivo and in vitro overexpression of S6K1 in HCC. In the functional analysis, we demonstrate that S6K1 is required for the proliferation and colony formation abilities in HCC. By using comparative transcriptomic analysis followed by gene ontology enrichment analysis and Ingenuity Pathway Analysis, we find that the depletion of S6K1 can elevate the expression of a cluster of apoptotic genes, tumor suppressor genes and immune responsive genes. Moreover, the knockdown of S6K1 is predicted to reduce the tumorigenicity of HCC through the regulation of hubs of genes including STAT1, HDAC4, CEBPA and ONECUT1. In conclusion, we demonstrate the oncogenic role of S6K1 in HCC, suggesting the possible use of S6K1 as a therapeutic target for HCC treatment.
| S-EPMC7065997 | biostudies-literature