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Cosmc overexpression enhances malignancies in human colon cancer.

ABSTRACT: Cosmc is known as a T-synthase-specific molecular chaperone that plays a crucial role in the process of O-glycosylation. Cosmc dysfunction leads to inactive T-synthase and results in aberrant O-glycosylation, which is associated with various tumour malignancies. However, it is unclear whether Cosmc has some other functions beyond its involvement in O-glycosylation. In this study, we aimed to investigate the functional role of Cosmc in human colorectal cancer (CRC). We first assessed the expression levels of Cosmc in human CRC specimens and then forcedly expressed Cosmc in human CRC cell lines (HCT116, SW480) to examine its impact on cellular behaviours. The mechanisms for aberrant expression of Cosmc in CRC tissues and the altered behaviours of tumour cells were explored. It showed that the mRNA and protein levels of Cosmc were markedly elevated in human CRC specimens relative to normal colorectal tissues. The occurrence of endoplasmic reticulum (ER) stress may largely contribute to the increased Cosmc expression in cancer tissue and cells. Cosmc overexpression in CRC cells significantly promoted cell migration and invasion, which could be attributed to the activation of the epithelial-mesenchymal transition (EMT) pathway rather than aberrant O-glycosylation. These data indicate that Cosmc expression was elevated in human CRC possibly caused by ER stress, which further enhanced malignancies through the activation of EMT but independently of aberrant O-glycosylation.

SUBMITTER: Gao T

PROVIDER: S-EPMC6933370 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Cosmc overexpression enhances malignancies in human colon cancer.

Gao Tianbo T Du Tan T Hu Xin X Dong Xichen X Li Lina L Wang Yakun Y Liu Jian J Liu Lijie L Gu Tao T Wen Tao T

Journal of cellular and molecular medicine 20191021 1

Cosmc is known as a T-synthase-specific molecular chaperone that plays a crucial role in the process of O-glycosylation. Cosmc dysfunction leads to inactive T-synthase and results in aberrant O-glycosylation, which is associated with various tumour malignancies. However, it is unclear whether Cosmc has some other functions beyond its involvement in O-glycosylation. In this study, we aimed to investigate the functional role of Cosmc in human colorectal cancer (CRC). We first assessed the expressi ...[more]

PMID: 31633299

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Project description:Colon cancer is one of the most common cancers in the world. Multidrug resistance is one of the main reasons for failure of therapy in patients with advanced colon cancer. In previous studies, multiple methods were investigated to reverse the multidrug resistance of colon cancer cells. However, to date, no clinical method has been identified to be satisfactory. Therefore, successful reversal of drug resistance in colon cancer cells still requires new therapeutic strategies or pharmaceuticals. Wild-type p53-induced phosphatase (Wip1), a member of the 2C type serine/threonine protein phosphatase family, is closely associated with the p53 gene, which is the most important tumor-suppressor gene. Wip1 was reported to be associated with the chemosensitivity of breast cancer cells. However, the correlation between the expression of Wip1 gene and the chemosensitivity of colon cancer cells has not been reported yet. In the present study, Wip1-811 small interfering RNA (siRNA) targeting Wip1 was investigated to reverse the multidrug resistance of colon cancer cells. The siRNA duplexes were transfected into RKO colon cancer cells. The messenger RNA (mRNA) expression of Wip1 was measured by reverse transcription-quantitative polymerase chain reaction. The protein level of Wip1 was detected by western blotting. The cell viability was measured by MTS assay. The cell apoptosis and cell cycle were analyzed by flow cytometry. Intracellular adriamycin cumulative concentration was determined using flow cytometry. Wip1-811 siRNA efficiently inhibited the expression of Wip1 at the mRNA and protein levels, and enhanced the sensitivity of RKO colon cancer cells towards chemotherapy, which was accompanied by increased cell apoptosis, following the inhibition of Wip1 gene expression. These results indicate that Wip1 gene silencing could enhance the chemosensitivity of colon cancer cells, which may provide a new potential approach for the reversal of multidrug resistance in colon cancer cells.

Project description:Background: Second primary malignancy (SPM) attracts a growing attention. However, the clinical features of colon cancer (CC) survivors with SPMs are not clear and could help guide clinicians to develop a better surveillance strategy. Methods: We reviewed 56,930 CC survivors treated with colectomy from the Surveillance, Epidemiology, and End Results (SEER) database during 1998-2011. Competing risk models and nomograms were conducted for predicting the risk of occurring SPMs. The clinical utility of the models was measured by decision curve analysis (DCA) using net benefit approaches. Results: Five thousand thirteen (17.1%) of male patients developed SPMs and sites of SPMs included prostate (32.2%), lung and bronchus (11.6%), urinary bladder and kidney (10.8%), colon (10.0%), and melanoma of the skin (3.9%), while 3,592 (13.0%) of female patients occurred SPMs and sites of SPMs involved breast (25.8%), lung and bronchus (13.6%), colon (11.6%), uterus (8.2%), urinary bladder, and kidney (5.6%). Survivors with a second carcinoma of lung and bronchus showed the worst prognosis. Older age increased the risk of SPMs in both male (Subdistribution hazard ratio =2.85 [95% confidence interval = 2.53-3.21]) and female (1.80 [1.59-2.04]) survivors, especially for the risk of a second prostate carcinoma in male (5.33 [4.03-7.03]). Compared with white race, black male survivors remained at higher risk to develop the second prostate carcinoma (1.98 [1.74-2.26]). Competing-risk nomograms for CC survivors were established to help clinicians predict the probabilities of overall SPMs and prostate carcinoma. Validation of nomograms showed good discrimination and accuracy, and DCAs revealed the clinical effectiveness. Conclusions: We profiled the clinical characteristics of a large population-based cohort of CC survivors with SPMs. These features may improve future follow-up management, especially for the surveillance of second prostate cancer in men and second breast cancer in women.

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Cosmc overexpression enhances malignancies in human colon cancer.

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Cosmc overexpression enhances malignancies in human colon cancer.

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