TFF3-dependent resistance of human colorectal adenocarcinoma cells HT-29/B6 to apoptosis is mediated by miR-491-5p regulation of lncRNA PRINS.
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.
Department of Veterinary Medicine, Institute of Veterinary Biochemistry, Freie Universität Berlin , Berlin, Germany.
Carlos
C
Hanisch
Department of Veterinary Medicine, Institute of Veterinary Biochemistry, Freie Universität Berlin, Berlin, Germany; Lise Meitner School of Science, Berlin, Germany.
Jutta
J
Sharbati
Department of Veterinary Medicine, Institute of Veterinary Biochemistry, Freie Universität Berlin , Berlin, Germany.
Barbara
B
Kutz-Lohroff
Institute of Biochemistry II, Jena University Hospital , Jena, Germany.
Otmar
O
Huber
Department of Veterinary Medicine, Institute of Veterinary Biochemistry, Freie Universität Berlin , Berlin, Germany.
Ralf
R
Einspanier
Department of Veterinary Medicine, Institute of Veterinary Biochemistry, Freie Universität Berlin , Berlin, Germany.
Soroush
S
Sharbati