Small 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. Forty-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. This 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.

Hepatocellular carcinoma (HCC) is a male‐dominant cancer, and androgen receptor (AR) has been linked to the pathogenesis of HCC. However, AR expression and its precise role in HCC remain controversial. Moreover, previous antiandrogen and anti‐AR clinical trials in HCC failed to demonstrate clinical benefits. In this study, we found that AR is overexpressed in the nucleus of approximately 37% of HCC tumors, which is significantly associated with advanced disease stage and poor survival. AR overexpression in HCC cells markedly alters AR‐dependent transcriptome, stimulates oncogenic growth, and determines therapeutic response to enzalutamide, a second generation of AR antagonist. However, AR inhibition evokes feedback activation of AKT‐mTOR (mechanistic target of rapamycin) signaling, a central regulator for cell growth and survival. On the other hand, mTOR promotes nuclear AR protein expression by restraining ubiquitin‐dependent AR degradation and enhancing AR nuclear localization, providing a mechanistic explanation for nuclear AR overexpression in HCC. Finally, cotargeting AR and mTOR shows significant synergistic anti‐HCC activity and decreases tumor burden by inducing apoptosis in vivo. Conclusion: Nuclear AR overexpression is associated with the progression and prognosis of HCC. However, enzalutamide alone has limited therapeutic utility attributed to feedback activation of the AKT‐mTOR pathway. Moreover, mTOR drives nuclear AR overexpression. Cotargeting AR and mTOR is a promising therapeutic strategy for HCC. (Hepatology 2018;67:2271‐2286).

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. Clin Cancer Res; 19(17); 4780–91. ©2013 AACR.

Cancer metastasis is the main cause of death in breast cancer (BC) patients. Therefore, prediction and treatment of metastasis is critical for enhancing the survival of BC patients. In this study, we aimed to identify biomarkers that can predict metastasis of BC and elucidate the underlying mechanism of the functional involvement of such markers in metastasis. miRNA expression profile was analyzed using a custom microarray system in 422 BC tissues. The relationship between the upregulated miR-665, metastasis and survival of BC was analyzed and verified in another set of 161 BC samples. The biological function of miR-665 in BC carcinogenesis was explored with in vitro and in vivo methods. The target gene of miR-665 and its signaling cascade were also analyzed. There are 399 differentially expressed miRNAs between BC and noncancerous tissues, of which miR-665 is the most upregulated miRNA in the BC tissues compared with non-tumor breast tissues (P < 0.001). The expression of miR-665 predicts metastasis and poor survival in 422 BC patients, which is verified in another 161 BC patients and 2323 BC cases from online databases. Ectopic miR-665 expression promotes epithelial–mesenchymal transition (EMT), proliferation, migration and invasion of BC cells, and increases tumor growth and metastasis of BC in mice. Bioinformatics, luciferase assay and other methods showed that nuclear receptor subfamily 4 group A member 3 (NR4A3) is a target of miR-665 in BC. Mechanistically, we demonstrated that miR-665 promotes EMT, invasion and metastasis of BC via inhibiting NR4A3 to activate MAPK/ERK kinase (MEK) signaling pathway. Our study demonstrates that miR-665 upregulation is associated with metastasis and poor survival in BC patients, and mechanistically, miR-665 enhances progression of BC via NR4A3/MEK signaling pathway. This study provides a new potential prognostic biomarker and therapeutic target for BC patients.

Mammalian / mechanistic target of rapamycin (mTOR) is a critical sensor of environmental cues that regulates cellular macromolecule synthesis and metabolism in eukaryotes. DNA methylation is the most well-studied epigenetic modification that is capable of regulating gene transcription and affecting genome stability. Both dysregulation of mTOR signaling and DNA methylation patterns have been shown to be closely linked to tumor progression and serve as promising targets for cancer therapy. Although their respective roles in tumorigenesis have been extensively studied, whether molecular interplay exists between them is still largely unknown. In this review, we provide a brief overview of mTOR signaling, DNA methylation as well as related serine and one-carbon metabolism, one of the most critical aspects of metabolic reprogramming in cancer. Based on the latest understanding regarding the regulation of metabolic processes by mTOR signaling as well as interaction between metabolism and epigenetics, we further discuss how serine and one-carbon metabolism may serve as a bridge that links mTOR signaling and DNA methylation to promote tumor growth. Elucidating their relationship may provide novel insight for cancer therapy in the future.