Abstract
An increasing number of studies have shown that long non-coding RNA (lncRNA) dysregulation plays a fundamental role in the development of various cancers, including colon cancer. Nonetheless, the mechanisms of lncRNA in regorafenib-resistance remain unclear. Our research revealed the lncRNA MIR570MG increased in regorafenib-resistant colon cancer cells compared to the regorafenib-sensitive cells. Furthermore, MIR570MG sponged miR-145, which declined in regorafenib-resistant colon cancer cell lines. More importantly, overexpression of miR-145 hampered cell proliferation and retrieved colon cancer regorafenib-sensitivity, contrary to the function of MIR570MG. Dual-luciferase reporter assay confirmed that miR-145 bound to 3′-UTR of SMAD3, a transcriptional modulator activated by TGFβ, resulting in blockage of TGFβ /SMAD3-mediated cell growth and cycle progression. Besides, ectopic expression of miR-145 inhibitor in the parental cells endowed resistance to regorafenib. Inversely, knockdown of MIR570MG impoverished resistance against regorafenib. Additionally, overexpression of MIR570MG conquered the suppression of tumor growth by miR-146 and rehabilitated the resistance to regorafenib in HCT116R human colon cancer mouse models. In summary, our findings suggested that MIR570MG promoted regorafenib resistance via releasing SMAD3 from miR-145, leading to activation of SMAD3-mediated signaling pathways.
Highlights
Despite the achievement in multimodality therapy combining chemo, radio- and targeted therapy over the last decade, the mortality and the recurrence rates of metastatic colorectal cancer are inadequate
We found long non-coding RNA (lncRNA) MIR570MG upregulated in regorafenib-resistant cells, antagonizing apoptosis, loss of colony formation, and cell cycle arrest by regorafenib
Regorafenib has been used for late line treatment for several cancers including advanced colorectal cancer [12], hepatocellular carcinoma [13], and gastrointestinal stromal tumors [14]
Summary
Despite the achievement in multimodality therapy combining chemo-, radio- and targeted therapy over the last decade, the mortality and the recurrence rates of metastatic colorectal cancer are inadequate. Novel agents targeting epidermal growth factor receptor, insulin-like growth factor receptor, transforming growth factor-beta receptor and other growth factors were developed to treat advanced/refractory colorectal cancer. The United States Food and Drug Administrate has approved regorafenib, an oral multi-kinases inhibitor, for treating unresectable or metastatic colon cancer following first- and second-line therapy [1]. The intrinsic and acquired resistance to regorafenib restrains its application further. The exact mechanisms underlying resistance to regorafenib remain mostly unknown. While the minority of genome encodes proteins, most of the genome comprises non-coding sequences. Most of the non-coding RNA is transcribed to RNA, including
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