Abstract
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths globally and is biologically and clinically heterogeneous. Due to lack of gene expression signatures for risk and prognosis stratification of CRC, identifying novel molecular biomarkers and therapeutic targets may potentially improve CRC prognosis and treatment. RNF180 has been shown to play key contributions to the development of several types of cancers. In the current study, we investigate its role in CRC. In this study, we show that RNF180 expression was significantly downregulated in human CRC tumors and cell lines. Overexpression of RNF180 in CRC cells markedly inhibited cell viability and induced cell apoptosis, while depletion of RNF180 dramatically enhanced cell survival. Moreover, WISP1 was found to be the critical downstream molecule that mediated the tumor suppressive effects of RNF180. Mechanistically, RNF180 ubiquitinated WISP1, resulting in WISP1 downregulation and ultimately leading to suppression of CRC tumor growth in patient-derived xenograft (PDX) mouse models. Last, 5-FU and RNF180 had synergetic effect on the apoptosis induction and tumor growth inhibition. Our findings revealed a crucial role of RNF180 in suppressing tumor growth by ubiquitinating WISP1 in CRC.
Highlights
Colorectal cancer (CRC) is the third leading cause of cancer deaths in the world, and is the second and fifth leading cause of cancer-related mortalities in United States and China, respectively (Parkin et al, 2001; Chen et al, 2016; Siegel and Miller, 2019)
These results suggest that RING finger protein 180 (RNF180) may function as a tumor suppressor in the pathogenesis of CRC
Our studies revealed that Ring Finger Protein 180 (RNF180) was downregulated in a wide range of cancers, including
Summary
Colorectal cancer (CRC) is the third leading cause of cancer deaths in the world, and is the second and fifth leading cause of cancer-related mortalities in United States and China, respectively (Parkin et al, 2001; Chen et al, 2016; Siegel and Miller, 2019). According to the American Cancer Society, the estimated number of CRC cases in the United States for 2019 is 145,600 (Siegel and Miller, 2019). The primary treatment options for CRC patients include surgical resection, radiotherapy and chemotherapy. The 5-year survival rate for CRC patients with advanced CRC is only 55–75% after surgical resection. To minimize relapse after surgical therapy, 5-Fluorouracil (5-FU)-based chemotherapy has been commonly utilized for treatment. To minimize relapse after surgical therapy, 5-Fluorouracil (5-FU)-based chemotherapy has been commonly utilized for treatment. 5-FU administration has been shown to reduce tumor size by ∼50% in patients with
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