TFF3-dependent resistance of human colorectal adenocarcinoma cells HT-29/B6 to apoptosis is mediated by miR-491-5p regulation of lncRNA PRINS

Abstract

Tumour necrosis factor-α (TNF-α) is a double-edged cytokine associated with pathogenesis of inflammatory-related cancers being also able to induce cancer cell death. In the process of tumour development or metastasis, cancer cells can become resistant to TNF-α. In trefoil factor 3 (TFF3) overexpressing colorectal adenocarcinoma cells (HT-29/B6), we observed enhanced resistance against TNF-α/interferon gamma-induced apoptosis. TFF3 is a secreted small peptide that supports intestinal tissue repair but is also involved in intestinal tumour progression and scattering. We hypothesised that TFF3 rescues intestinal epithelial cancer cells from TNF-α-induced apoptosis by involving regulatory RNA networks. In silico-based expression analysis revealed TFF3-mediated regulation of selected microRNAs as well as long non-coding RNAs (lncRNAs), whereas miR-491-5p was identified to target the lncRNA ‘psoriasis susceptibility-related RNA gene induced by stress’ (PRINS). RNA interference-based gain- and loss-of-function experiments examined miR-491-PRINS axis to exert the TFF3-mediated phenotype. Chemical inhibition of selected pathways showed that phosphatidylinositol 3-kinase/AKT accounts for TFF3-mediated downregulation of miR-491-5p and accumulation of PRINS. Moreover, we showed that PRINS colocalises with PMAIP1 (NOXA) in nuclei of HT-29/B6 possessing inhibitory effects. Immunoprecipitation experiments proved molecular interaction of PMAIP1 with PRINS. Our study provides an insight into RNA regulatory networks that determine resistance of colorectal cancer cells to apoptosis.

Effect of CCT137690 on long non-coding RNA expression profiles in MCF-7 and MDA-MB-231 cell lines

“…According to the evidence, PRINS acts as an anti-apoptotic lncRNA [48]. In the current study, PRINS lncRNA levels attenuated in both estrogen-dependent and -independent cell lines following CCT137690 exposure.…”

Overexpression of TFF3 is involved in prostate carcinogenesis via blocking mitochondria-mediated apoptosis

“…Casado et al demonstrated that colorectal cancer cells overexpressing TFF3 showed reduced sensitivity to chemotherapy by being resistant to apoptosis 46 . Hanisch et al reported that TFF3 overexpression enhanced resistance to TNF-α/interferon gamma-induced apoptosis 47 . In the study by Perera et al TFF3 overexpression was associated with reduced sensitivity to ionizing radiation in PCa cells 28 .…”

A Novel LncRNA-miRNA-mRNA Triple Network Identifies LncRNA RP11-363E7.4 as An Important Regulator of miRNA and Gene Expression in Gastric Cancer

“…11B, we show the close relationship between lncRNA RP11-613D13.8 and miR491-5p. Previous studies regarding miR-491-5p have demonstrated that it played an important role in different cancers, including GC [49,[53][54][55][56], and could also have critical roles in a variety of cellular processes, including cell proliferation, tumor metastasis, tumor invasion, cell apoptosis, and the cell cycle. Sun et al reported that the expression of miR-491-5p was markedly downregulated in GC, which inhibited cell proliferation by disrupting the cell cycle and promoting apoptosis in GC cells via targeting Wnt3a [49].…”