Abstract
RN181, a RING finger domain‐containing protein, is an E3 ubiquitin ligase. However, its biological function and clinical significance in cancer biology are obscure. Here, we report that RN181 expression is significantly down‐regulated in 165 tumour tissues of gastric carcinoma (GC) versus adjacent non‐tumour tissues, and inversely associated with tumour differentiation, tumour size, clinical stage, and patient's overall survival. Alterations of RN181 expression in GC cells by retrovirus‐transduced up‐regulation and down‐regulation demonstrated that RN181 functions as a tumour suppressor to inhibit growth of GC in both in vitro culture and in vivo animal models by decreasing tumour cell proliferation and increasing tumour cell apoptosis. Cell cycle analysis revealed that RN181 controls the cell cycle transition from G1 to S phase. Mechanistic studies demonstrated that RN181 inhibits ERK/MAPK signalling, thereby regulating the activity of cyclin D1–CDK4, and consequently controlling progression in the cell cycle from G1 to S phase. Restoring CDK4 in GC cells rescued the inhibitory phenotype produced by RN181 in vitro and in vivo, suggesting a dominant role of CDK4 in control of the tumour growth by RN181. Importantly, RN181 expression is inversely correlated with the expression of cyclin D1 and CDK4 in GC clinical samples, substantiating the role of the RN181–cyclin D1/CDK4 pathway in control of the tumour growth of GC. Our results provide new insights into the pathogenesis and development of GC and rationale for developing novel intervention strategies against GC by disruption of ERK/MAPK–cyclin D1/CDK4 signalling. In addition, RN181 may serve as a novel biomarker for predicting clinical outcome of GC. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Highlights
Gastric adenocarcinoma is the fifth most common cancer and the third leading cause of cancer mortality worldwide [1]
We examined the expression of RN181 in a cohort of 165 pairs of gastric carcinoma (GC) and adjacent non-tumour tissues by IHC (Figure 1A and supplementary material, Figure S1)
The results suggest that RN181 functions as a tumour suppressor in the stomach to control the tumour growth of GC by decreasing tumour cell proliferation and increasing tumour cell apoptosis
Summary
Gastric adenocarcinoma (gastric cancer, GC) is the fifth most common cancer and the third leading cause of cancer mortality worldwide [1]. In China, GC is the second most common cancer and the second leading cause of cancer death, having estimated numbers of 679 100 new cases and 498 000 deaths in 2015 [2]. A randomised phase 3 trial for the first-line treatment of HER2-positive advanced GC showed that trastuzumab, a humanised monoclonal antibody targeting HER2, when combined with standard chemotherapy, significantly improves an overall survival of GC patients from 11.1 months to 13.8 months [3]. It is imperative that identification of new targets will help to understand the molecular mechanisms of pathogenesis and develop a novel targeted therapy or biomarker for evaluating the therapeutic efficacy or predicting the prognosis of GC patients [8]
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