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microR-4449 Promotes Colorectal Cancer Cell Proliferation via Regulation of SOCS3 and Activation of STAT3 Signaling

Authors Yan Z, Hong S, Song Y, Bi M

Received 4 June 2020

Accepted for publication 21 October 2020

Published 7 April 2021 Volume 2021:13 Pages 3029—3039

DOI https://doi.org/10.2147/CMAR.S266153

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 4

Editor who approved publication: Dr Yong Teng


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 China

Correspondence: Sen Hong
Department of Colorectal and Anal Surgery, The First Hospital of Jilin University, Changchun, Jilin, 130022, People’s Republic of China
Email [email protected]
Zhenkun Yan
Department of Endoscopy Center, The Third Hospital of Jilin University, Changchun, Jilin, 130022, People’s Republic of China
Email [email protected]

Introduction: 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

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