Long Non-coding RNA CCAT1 Acts as an Oncogene and Promotes Sunitinib Resistance in Renal Cell Carcinoma

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.

Long Non-Coding RNAs as Molecular Biomarkers in Cholangiocarcinoma

“…Colon cancer-associated transcript 1 (CCAT1) was initially identified as being overexpressed in colon cancer tissues, peripheral blood, and related lymph node tissues, but it was almost undetectable in normal human body tissues ( Nissan et al, 2012 ). As a rising star among carcinogenic lncRNAs, CCAT1 has been closely related to many cancers’ occurrence, development, and drug resistance ( Jin et al, 2020 ; Shan et al, 2020 ; Su et al, 2020 ; Wang et al, 2021 ). CCAT1 expression was dramatically increased in CCA tissues and was shown to be strongly linked to lymph node infiltration and late TNM stage ( Zhang et al, 2017a ; Jiang et al, 2017 ).…”

Circular RNA Eps15-homology domain-containing protein 2 induce resistance of renal cell carcinoma to sunitinib via microRNA-4731-5p/ABCF2 axis

“…Subsequently, the concentration of SU was increased by 0.25 µM every 72 h. the surviving clones were continuously passaged until the IC50 values reached 18 µM in the 10 th month. The stable SU-resistant sublines were maintained with the medium supplemented by 0.02 µM SU [ 18 ].…”

The role of long non-coding RNAs in angiogenesis and anti-angiogenic therapy resistance in cancer

“… 100 In renal cell carcinoma (RCC), lncRNA CCAT1 granted resistance to sunitinib in a c-Myc-dependent manner, providing a new target for improving sunitinib therapy ( Figure 2 H). 102 In addition, Liu et al. first proposed lncRNA SNHG12 could upregulate the expression of CDCA3 by stabilizing transcription factor SP1 to facilitate tumor progressions and resistance to sunitinib in RCC.…”