Cancer Management and Research (Apr 2021)
microR-4449 Promotes Colorectal Cancer Cell Proliferation via Regulation of SOCS3 and Activation of STAT3 Signaling
Abstract
Zhenkun Yan,1 Sen Hong,2 Yumei Song,3 Miaomiao Bi4 1Department of Endoscopy Center, The Third Hospital of Jilin University, Changchun, Jilin, 130022, People’s Republic of China; 2Department of Colorectal and Anal Surgery, The First Hospital of Jilin University, Changchun, Jilin, 130022, People’s Republic of China; 3Department of Thoracic Oncology, Tumor Hospital of Jilin Province, Changchun, Jilin, 130022, People’s Republic of China; 4Department of Ophthalmology, The Third Hospital of Jilin University, Changchun, Jilin, 130022, People’s Republic of ChinaCorrespondence: Sen HongDepartment of Colorectal and Anal Surgery, The First Hospital of Jilin University, Changchun, Jilin, 130022, People’s Republic of ChinaEmail [email protected] YanDepartment of Endoscopy Center, The Third Hospital of Jilin University, Changchun, Jilin, 130022, People’s Republic of ChinaEmail [email protected]: Dysregulation of microRNAs (miRNAs), which represented a critical level of gene expression modulation, regulated the development of colorectal cancer. However, the functions of numerous miRNAs remain unclear in colorectal cancer.Methods: The microarray data of GSE115513 were retrieved; subsequently, the differentially expressed miRNAs between 411 colon tumors and 381 normal colon mucosa were analyzed. Real-time PCR (RT-qPCR) and bioinformatic analysis were applied to examine the expression of miR-4449 in collected colorectal tumors and published microarray data. The activity of signal transducer and activator of transcription 3 (STAT3) signaling was detected by Western blotting and RT-qPCR. Dual-Luciferase assay and bioinformatic analysis were used to confirm the interaction between suppressor of cytokine signaling 3 (SOCS3) and miR-4449. Loss of function and rescue assays were performed to study the involvement of miR-4449 and SOCS3 in cell proliferation and apoptosis of colorectal cancer.Results: Herein, we identified miR-4449 as a novel upregulated miRNA in colorectal cancer. Our data suggested that miR-4449 downregulation blocked the proliferation of colorectal cancer cells accompanied with the elevation of cell apoptosis. Decreased expression of miR-4449 led to inactivation of STAT3 pathway as indicated by dephosphorylation of STAT3 and downregulation of STAT3 target genes, including vascular endothelial growth factor (VEGF), c-Myc, baculovirus inhibitor of apoptosis containing 5 (BIRC5). Furthermore, SOCS3, a negative regulator of STAT3 pathway, was found to be a target gene of miR-4449. The data also showed that the inactivation of STAT3 pathway by miR-4449 inhibitor was realized by targeting SOCS3. Moreover, the biological function of miR-4449 downregulation was reversed by SOCS3 knockdown in colorectal cancer cells.Conclusion: The current study revealed that miR-4449 promoted cell proliferation of colorectal cancer and was a promising potential therapeutic target for colorectal cancer.Keywords: STAT3, microR-4449, colorectal cancer, SOCS3
