Abstract
Although sunitinib contributes to prolonging the progression-free survival of metastatic renal cell carcinoma significantly, the universal presence of resistance limits the initial response rate and restricts durable responses. The mechanisms involved in sunitinib resistance vary and need further investigation. We found long non-coding RNA (lncRNA) colon cancer-associated transcript-1 (CCAT1) overexpressed in sunitinib-resistant cells while declined in the parental cells. Moreover, lncRNA CCAT1 increased significantly in samples with resistance to sunitinib compared with those with responses to sunitinib. The reduction of CCAT1 suppressed cell growth and colony formation while triggering apoptosis. Inversely, the ectopic expression of c-Myc reversed the inhibition of cell growth and enhancement of apoptosis by the knockdown of CCAT1. We also verified that anti-apoptosis protein B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia 1 (Mcl-1) decreased along with the deregulation of CCAT1, whereas the expression of Bcl-2 and Mcl-1 restored in cells that were transfected sh-CCAT1 and c-Myc simultaneously. Apart from the in vitro experiments, we demonstrated that knockdown of CCAT1 boosted response to sunitinib by performing sunitinib-resistant ACHN mouse models. Briefly, lncRNA CCAT1 conferred renal cell carcinoma resistance to sunitinib in a c-Myc-dependent manner, providing a novel target for improvement of sunitinib therapy.
Highlights
Renal cell carcinoma (RCC) implies that cancer emerged in the renal epithelium and attributed to the majority of cancers in the kidney
I, the expression of B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia 1 (Mcl-1) fell to a greater extent in SR cells deregulated cancer-associated transcript-1 (CCAT1) post-sunitinib treatment compared with those post-DMSO. These results indicated that CCAT1 played an essential role in driving resistance to sunitinib
We found that CCAT1 expression increased in established sunitinib-resistant RCC sublines and acquired sunitinibresistant clinical samples (Figure 1)
Summary
Renal cell carcinoma (RCC) implies that cancer emerged in the renal epithelium and attributed to the majority of cancers in the kidney. Anti-angiogenic therapy is the first-line treatment for advanced RCC, including bevacizumab, the antibody-targeted vascular endothelial growth factor (VEGF), and tyrosine kinases inhibitor-targeted vascular epidermal growth factor receptors such as sunitinib, pazopanib, and axitinib [2]. Anti-angiogenic therapy requires improvement due to LncRNA CCAT1 Confers Sunitinib Resistance a few patients with tumors that have primary resistance and the general appearance of adapted resistance during treatment. The alternative activation of hepatocyte growth factor-mesenchymal-epithelial transition factor axis (HGF-MET axis) drove resistance to VEGF inhibitor [3]. The MET/AXL-induced epithelial-mesenchymal transition conferred resistance to sunitinib [5]. The clinical trials that attempted to conquer the anti-angiogenesis were limited, urging an extensive understanding of resistance mechanisms
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