9891

NUAK1

epithelial ovarian cancer (EOC) is the sixth most common cancer in females worldwide and, although advances have been made in the detection, diagnosis and therapies for EOC, it remains the most lethal gynecologic malignancy in advanced countries. Nevertheless, relatively little is known concerning the molecular events that lead to the development of this highly aggressive disease. Elucidating the molecular mechanism involved in this disease may prove useful to understand the pathogenesis and progression of the disease, and to identify new targets for effective therapies. In the present study, we examined the role of ARK5 in ovarian cancer and normal matched tissues using western blot analysis and migration and invasion, and woundhealing assays. The results showed that ARK5 was upregulated in ovarian cancer tissues, compared with adjacent normal tissues. Moreover, it promoted epithelialmesenchymal transition (EMT) and inhibited miR-1181 expression in ovarian cancer cells. Subsequent investigations showed that miR-1181 promoted mesenchymal-epithelial transition (MET) in ovarian cancer cells. Downstream target genes of miR-1181 were searched, and it was identified that miR-1181 degraded HOXA10 by targeting its 3' untranslated region (3'UTR) in ovarian cancer cells. The results confirmed that HOXA10 promoted EMT in ovarian cancer cells. Thus, activation of the ARK5/miR-1181/HOXA10 axis may be positively associated with EMT in ovarian cancer.

Head and neck squamous cell carcinoma (HNSCC) has a high capacity for invasion. To identify microRNAs (miRNAs) that regulate HNSCC invasion, we compared miRNA expression profiles between a parent HNSCC cell line and a highly invasive clone. The miR-200 family and miR-203 were downregulated in the clone. Here we focused on the role of miR-203 in invasion and epithelial-mesenchymal transition (EMT) induction in HNSCC. miR-203 was downregulated during EMT induction. Moreover, ectopic overexpression of miR-203 suppressed the invasion and induced mesenchymal-epithelial transition (MET) in HNSCC cells. Interestingly, we identified NUAK family SNF1-like kinase 1 (NUAK1) as a novel target gene of miR-203 by cyclopedic analysis using anti-Ago2 antibody. Increased expression of NUAK1 was observed during EMT induction, and ectopic expression of miR-203 delayed EMT induction by suppressing NUAK1 expression. Moreover, NUAK1 overexpression promoted the invasion of HNSCC cells. Importantly, NUAK1 expression was well correlated with poor differentiation, invasiveness, and lymph node metastasis in HNSCC cases. Overall, miR-203 has a tumor-suppressing role in invasion and EMT induction by targeting NUAK1 in HNSCC, suggesting miR-203 as a potential new diagnostic and therapeutic target for the treatment of HNSCC.

AMP-activated protein kinase family member 5 (ARK5) overexpression has been reported in many human cancers, and ARK5 is associated with poor prognosis in hepatocellular carcinoma (HCC). However, whether ARK5 is involved in HCC chemoresistance is unclear. The present study aimed to investigate the role of ARK5 in HCC chemoresistance and the underlying mechanism. In this study, we found that SNU387 and SNU449 HCC cell lines overexpressing ARK5 displayed low doxorubicin sensitivity compared to Huh7 and Hep3B HCC cell lines with ARK5 low-expression. And knockdown of ARK5 increased the doxorubicin sensitivity in all HCC cell lines in the manner of inhibiting cell proliferation. Western blotting and immunofluorescence both showed that ARK5 knockdown upregulated E-cadherin and downregulated vimentin, which was consistent with the knockdown of TWIST, indicating ARK5 was involved in epithelial-mesenchymal transition (EMT). Moreover, suppressing ARK5 by siRNA restored E-cadherin and vimentin expression induced by doxorubicin treatment or hypoxia culture. Our results indicated ARK5 confers doxorubicin resistance in HCC via inducing EMT.CI - Copyright (c) 2016 Elsevier Ireland Ltd. All rights reserved.

BACKGROUND/AIMS: Gastric cancer (GC) is a common and lethal malignancy, and AMP-activated protein kinase-related kinase 5 (ARK5) has been discovered to promote cancer metastasis in certain types of cancer. In this study, we explored the role of ARK5 in GC invasion and metastasis. METHODS: ARK5 and epithelial-mesenchymal transition (EMT)-related markers were determined by immunohistochemistry and western blot in GC specimens. Other methods including stably transfected against ARK5 into SGC7901 and AGS cells, western blot, migration and invasion assays in vitro and nude mice tumorigenicity in vivo were also employed. RESULTS: The results demonstrated that ARK5 expression was increased and positively correlated with metastasis, EMT-related markers and poor prognosis in patients with GC. Knockdown of ARK5 expression remarkably suppressed GC cells invasion and metastasis via regulating EMT, rather than proliferation in vitro and in vivo. And knockdown of ARK5 expression in GC cells resulted in the down-regulation of the mTOR/p70S6k signals, Slug and SIP1. CONCLUSION: The elevated ARK5 expression was closely associated with cancer metastasis and patient survival, and it seemed to function in GC cells migration and invasion via EMT alteration, together with the alteration of the mTOR/p70S6k signals, Slug and SIP1, thus providing a potential therapeutic target for GC.CI - (c) 2017 The Author(s). Published by S. Karger AG, Basel.