miR‑381 and miR‑489 suppress cell proliferation and invasion by targeting CUL4B via the Wnt/β‑catenin pathway in gastric cancer

Abstract

Accumulating evidence has highlighted the critical role of cullin 4B (CUL4B) in driving tumourigenesis in several malignancies, including gastric cancer (GC); however, the mechanisms underlying CUL4B upregulation remain unclear. The dysregulation of microRNAs (miRNAs or miRs) is known to be involved in tumourigenesis. In this study, we report that the expression of miR-381 and miR-489 is downregulated and is negatively correlated with that of CUL4B in GC tissues and cell lines. Further analysis verified that miR-381 and miR-489 directly targeted CUL4B. CUL4B silencing inhibited cell proliferation, migration and invasion by inactivating the Wnt/β-catenin pathway. miR-381/miR-489 overexpression recapitulated the effects of CUL4B silencing, while CUL4B restoration negated the suppressive effects induced by the ectopic expression of miR-381/miR-489. Furthermore, miR-381/miR-489 exerted tumour suppressive functions by inactivating the Wnt/β-catenin pathway through the targeting of CUL4B. Taken together, the findings of this study suggest that the miR-381/miR-489-mediated expression of CUL4B modulates the proliferation and invasion of GC cells via the Wnt/β-catenin pathway, which indicates that the miR-381/miR-489-CUL4B axis is critical in the control of GC tumourigenesis.

CUL4B regulates cancer stem‐like traits of prostate cancer cells by targeting BMI1 via miR200b/c

“…All analyses were presented as mean ± standard deviation calculated for three or more replicates. Statistical analyses were carried out using GraphPad prism 5 or the Statistical Package for Social Sciences, version 19.0 (SPSS, Chicago, IL), with P < .05 being considered statistically significant. Two-tailed the Student t test was used for statistical comparisons.…”

“…CUL4B is a scaffold protein and might be involved in the nucleus‐based functions as it carries a nuclear localization signal in its N terminus and localizing in the nucleus . Previous studies have demonstrated that CUL4B is dysregulated in various malignancies and possesses potent oncogenic properties . CUL4B promotes histone and DNA methylation, recruits PRC2, leading to transcriptional silencing of tumor suppressor genes such as P16, PTEN, and Wnt antagonists, by catalyzing histone H2AK119 monoubiquitylation (H2AK119ub1) .…”

“…15 Previous studies have demonstrated that CUL4B is dysregulated in various malignancies and possesses potent oncogenic properties. [16][17][18][19] CUL4B promotes histone and DNA methylation, recruits PRC2, leading to transcriptional silencing of tumor suppressor genes such as P16, PTEN, and Wnt antagonists, by catalyzing histone H2AK119 monoubiquitylation (H2AK119ub1). 20 We previously demonstrated that CUL4B is overexpressed in gastric cancer and promotes gastric cancer invasion and metastasis mainly via upregulation of HER2.…”

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“…In another study of gastric carcinoma, miR-23b-3p and miR-130a-5p appeared to affect cell growth, migration, and invasion by targeting CB1R via the Wnt/β-catenin signaling pathway [19]. Additionally, miR-381 and miR-489 have been found to decrease cell proliferation and invasion in gastric cancer by targeting CUL4B via the Wnt/β-catenin pathway [20].…”

Expression of miR‑221 and miR‑489 in breast cancer patients and their relationship with prognosis

“…At present, a number of reports (5)(6)(7) have proven that microRNAs (miRNAS) are involved in the development of various tumors. miR-221 and miR-489 have been verified to have abnormal expression (8)(9)(10) in colorectal cancer and gastric cancer; however, miR-221 and miR-489 expression levels in breast cancer have been rarely reported. Therefore, in the present study it was speculated that miR-221 and miR-489 have also abnormal expression in breast cancer, and experimental analysis was carried out for verification.…”