No abstract

BackgroundSmall cell carcinoma of the cervix (SCCC) is very rare, and due to the long time period required to recruit sufficient numbers of patients, there is a paucity of information regarding the prognostic factors associated with survival. MicroRNAs (miRNAs) have been used as cancer-related biomarkers in a variety of tumor types, and the objective of this study was to determine whether microRNA expression profiles can predict clinical outcome in SCCC.Methodology/Principal FindingsForty-four patients with SCCC who underwent radical hysterectomy between January 2000 and October 2009 were enrolled. Using the GeneCopoeia All-in-One™ Customized Human qPCR Primer Array, the expression profiles of 30 miRNAs associated with tumor metastasis was obtained from the formalin-fixed paraffin embedded samples of all 44 patients. Seven miRNAs, has-let-7c, has-miR-10b, has-miR-100, has-miR-125b, has-miR-143, has-miR-145 and has-miR-199a-5p were significantly down-regulated in advanced stage SCCCpatients (FIGO IB2-IV) compared to early stage SCCC patients (FIGOIB1). Among, downregulation of six miRNAs, has-let-7c, has-miR-100, has-miR-125b, has-miR-143, has-miR-145 and has-miR-199a-5p were significantly associated with lymph node metastasis and reduced survival in SCCC. Kaplan–Meier survival analyses revealed that SCCC patients with low expression of has-miR-100 (P = 0.019) and has-miR-125b (P = 0.020) projected a significant tendency towards poorer prognosis.Conclusions/SignificanceThis study demonstrates that downregulation of 7 miRNA associated with advanced stage, 6 miRNAs with metastasis and 2 with poor prognosis in SCCC. Functional analysis of these miRNAs may enhance our understanding of SCCC, as altered expression of specific miRNAs may regulate the metastatic pathway and provide novel targets for therapy.

Purpose: MicroRNAs (miRNAs) play important roles in the development and progression of cancer. The aim of this study is to identify miRNA expression signatures in hepatocellular carcinoma and delineate their clinical significance for hepatocellular carcinoma.Experimental Design: Patients with hepatocellular carcinoma, undergoing hepatectomy were randomly divided into training set (60 patients) and test set (50 patients). Other 56 patients were used as an independent cohort. The miRNA expression levels were detected by microarray and verified by quantitative real-time reverse transcription-PCR (qRT-PCR).Results: A 30-miRNA signature consisting of 10 downregulated and 20 upregulated miRNAs was established for distinguishing hepatocellular carcinoma from noncancerous liver tissues in the training set with 99.2% accuracy. The classification accuracies of this signature were 97% and 90% in the test set and independent cohort, respectively. The expression level of four miRNAs in the 30-miRNA signature was verified by qRT-PCR in the training set. Twenty miRNAs were then selected to construct prognostic signature in the training set. Of the 20 miRNAs, six were risk factors and 14 were protective factors. A formula based on the 20 miRNAs was built to compute prognostic index. Kaplan-Meier analysis showed that patients with a higher prognostic index had a significantly lower survival than those with a low index. This was verified in the test and independent sets. Multivariate analysis indicated that the 20-miRNA signature was an independent prognostic predictor.Conclusions: The 30-and 20-miRNA signatures identified in this study should provide new molecular approaches for diagnosis and prognosis of patients with hepatocellular carcinoma and clues for elucidating molecular mechanism of hepatocarcinogenesis.

Histone deacetylases (HDACs) mediate histone deacetylation, leading to transcriptional repression, which is involved in many diseases, including age-related tissue degeneration, heart failure and cancer. In this study, we were aimed to investigate the expression, clinical significance and biological function of HDAC4 in esophageal carcinoma (EC). We found that HDAC4 mRNA and protein are overexpressed in esophageal squamous cell carcinoma (ESCC) tissues and cell lines. HDAC4 overexpression is associated with higher tumor grade, advanced clinical stage and poor survival. Mechanistically, HDAC4 promotes proliferation and G1/S cell cycle progression in EC cells by inhibiting cyclin-dependent kinase (CDK) inhibitors p21 and p27 and up-regulating CDK2/4 and CDK-dependent Rb phosphorylation. HDAC4 also enhances ESCC cell migration. Furthermore, HDAC4 positively regulates epithelial-mesenchymal transition (EMT) by increasing the expression of Vimentin and decreasing the expression of E-Cadherin/α-Catenin. Together, our study shows that HDAC4 overexpression is important for the oncogenesis of EC, which may serve as a useful prognostic biomarker and therapeutic target for this malignancy.

mTORC1 is a master regulator of cell growth and proliferation, and an established anticancer drug target. Aberrant mTORC1 signaling is common in hepatocellular carcinoma (HCC), but the underlying mechanism remains elusive. Rab1A is a newly identified mTORC1 activator that mediates an alternative amino acid (AA) signaling branch to Rag GTPases. Because liver is a physiological hub for nutrient sensing and metabolic homeostasis, we investigated the possible role of Rab1A in HCC. We found that Rab1A is frequently overexpressed in HCC, which enhances hyperactive AA-mTORC1 signaling, promoting malignant growth and metastasis of HCC in vitro and in vivo. Moreover, aberrant Rab1A expression is closely associated with poor prognosis. Strikingly, aberrant Rab1A overexpression leads to increased rapamycin sensitivity, indicating that inappropriate activation of AA signaling is a cancer-driving event in HCC. Our findings further suggest that Rab1A is a valuable biomarker for prognosis and personalized mTORC1-targeted therapy in liver cancer.

Alcohol dehydrogenase 4 (ADH4) is an important member of ADH family that metabolize a wide variety of substrates including ethanol and retinol. Studies demonstrated that ADH4 was involved in cancer. Microarray data showed that the expression of ADH4 was reduced in hepatocellular carcinoma (HCC). However, the role of ADH4 in HCC carcinogenesis remains undefined. The aim of this study is to explore the clinical significance of ADH4 in progression and prognosis of HCC. The expression levels of ADH4 in 15 paired HCC and noncancerous (NC) liver tissues were measured by qRT-PCR and those in 4 paired samples by Western blotting. Another 91 paraffin-embedded HCC tissues were examined by immunohistochemistry. The qRT-PCR result showed that the expression level of ADH4 mRNA in HCC was significantly lower than that in NC tissues (P<0.0001). Western blotting also displayed that ADH4 protein was notably reduced in HCC. Immunohistochemistry assay confirmed that ADH4 protein was remarkably reduced in 59.3% HCC. The expression of ADH4 was correlated with the pathology grade (P=0.031) and serum AFP (P=0.022). HCC patients with lower ADH4 expression had much worse overall survival rate than that with high expression (P<0.001). Furthermore, multivariate analysis showed that ADH4 expression was an independent predictor of overall survival (HR, 0.154; 95%CI, 0.044-0.543; P=0.004). This is the first time that the expression levels of ADH4 mRNA and protein have found to be markedly reduced in HCC tissues and significantly associated with survival, suggesting that ADH4 is a novel and potential prognostic marker for HCC patients.

Abnormal interaction between non-coding RNAs has been demonstrated to be a common molecular event in various human cancers, but its significance and underlying mechanisms have not been well documented. RNA-binding proteins (RBPs) are key regulators of RNA transcription and post-transcriptional processing. In this study, we found that RNA-binding protein 24 (RBM24) was frequently downregulated in nasopharyngeal carcinoma (NPC). The restoration of RBM24 expression suppressed NPC cellular proliferation, migration and invasion and impeded metastatic colonization in mouse models. Microarray analyses revealed that miR-25 expression was upregulated by RBM24 expression in NPC cells. Similarly, ectopic miR-25 expression suppressed NPC cellular growth and motility by targeting the pro-oncogenic lncRNA MALAT1, and the knockdown of MALAT1 expression exhibited similar effects as RBM24 restoration in NPC cells. Overall, these findings suggest a novel role of RBM24 as a tumor suppressor. Mechanistically, RBM24 acts at least in part through upregulating the expression of miR-25, which in turn targets MALAT1 for degradation.

Checkpoint kinase 1 (CHEK1) is an evolutionarily conserved Ser/Thr kinase, which mediates cell-cycle arrest after DNA damage, and we previously reported that CHEK1 was overexpressed and associated with poor prognosis in hepatocellular carcinoma (HCC), indicating it was oncogenic gene. In this study, we aimed to elucidate the mechanism of CHEK1 overexpression in HCC. We first verified the upregulated CHEK1 by qRT-PCR and western blot in 30 HCC samples compared with corresponding non-tumor liver tissues. In silico analysis showed that CHEK1 was a candidate target of miR-497, which was previously found to be downregulated in HCC by us. To test whether miR-497 could bind to 3'untranslated region (3'UTR) of CHEK1, luciferase reporter assay was conducted. The result revealed that miR-497 could bind to the 3'untranslated region (3'UTR) of CHEK1 mRNA. Western blot showed that ectopic expression of miR-497 suppressed the CHEK1 expression and inhibition of miR-497 led to significant upregulation of CHEK1. Finally, miR-497 expression was measured in the same 30 HCC samples, and the correlation between miR-497 and CHEK1 was analyzed. The results indicated that miR-497 was downregulated in HCC and had a significant negative correlation with CHEK1. Taken together, these results demonstrated that CHEK1 was negatively regulated by miR-497, and the overexpressed CHEK1 was resulted from the downregulated miR-497 in HCC, which provided a potential molecular target for HCC therapy.