miR-135a leads to cervical cancer cell transformation through regulation of β-catenin via a SIAH1-dependent ubiquitin proteosomal pathway

Abstract

Human papillomaviruses (HPVs) is the principal etiological agent of cervical cancer (CC). However, exposure to the high-risk type HPV alone is insufficient for tumor formation, and additional factors are required for the HPV-infected cells to become tumorigenic. Dysregulated microRNAs (miRNAs) expression is frequently observed in cancer but their roles in the formation of CC have not been fully revealed. In this study, we compared the expression of miR-135a in laser capture microdissected cervical specimens and confirmed overexpression of the miRNA in malignant cervical squamous cell carcinoma compared with precancerous lesions. Transient force-expression of miR-135a induced growth in low-density culture, anchorage-independent growth, proliferation and invasion of a HPV-16 E6/E7-immortalized cervical epithelial cell line, NC104-E6/E7. The observed effects were due to the inhibitory action of miR-135a on its direct target seven in absentia homolog 1 (SIAH1) leading to upregulation of β-catenin/T cell factor signaling. miR-135a force-expression enhanced the growth of HeLa- and NC104-E6/E7-derived tumor in vivo. The effect of miR-135a could be partially nullified by SIAH1 force-expression. More importantly, the expression of SIAH1 and β-catenin correlated with that of miR-135a in precancerous and cancerous lesions of cervical biopsies. By comparing the tumorigenic activities of miR-135a in E6/E7 positive/negative cell lines and in NC104-E6/E7 with or without E6/E7 knockdown, we demonstrated that HPV E6/E7 proteins are prerequisite for miR-135a as an oncomiR. Taken together, miR-135a/SIAH1/β-catenin signaling is important in the transformation and progression of cervical carcinoma.

miR-135a modulates tendon stem/progenitor cell senescence via suppressing ROCK1

“…Previous studies have shown that miR-135a is involved in cancer development and metastasis [27,28]. miR-135a inhibits cell proliferation by targeting BMI1 in pancreatic ductal adenocarcinoma [29].…”

The human papillomavirus E7 oncoprotein as a regulator of transcription

“…Table 1 shows a summary of these findings, including miRNAs that have been shown to be regulated directly by E7. Other miRNAs have been shown to be regulated by HPV but the specific contribution of E7 (vs. the other viral oncogenes) is not yet known (Martinez, Gardiner et al 2008; Wang, Wang et al 2009; Bonnet, Tatari et al 2010; McKenna, McDade et al 2010; Jung, Phillips et al 2014; Leung, Deng et al 2014; Liu, Gao et al 2014; McKenna, Patel et al 2014; Zheng, Liu et al 2015; Liu, Zhang et al 2016). Only a few of these miRNAs are yet known to have a clear impact on the viral life cycle or on cancer development.…”

Involvement of seven in absentia homolog-1 in ethanol-induced apoptosis in neural crest cells

“…Siah ligases regulate the ubiquitination and proteasomal degradation of several proteins that are important in a variety of signaling pathways, including transcriptional regulators (Tiedt et al , 2001; Zhang et al , 1998), membrane receptors (Liani et al , 2004; Winter et al , 2008), a microtubule-associated motor protein (Linares-Cruz et al , 1998), and other proteins (Tan et al , 2014). Studies have suggested that Siah plays important roles in a variety of biological processes including cell proliferation, migration, axon guidance, and development (Gutierrez et al , 2006; Hu et al , 1999; Lee et al , 2008; Leung et al , 2014; Lorick et al , 1999; Xu et al , 2006b). In addition, Siah plays a critical role in the induction of apoptosis and tumor suppression (Nemani et al , 1996).…”