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Article

STAT3 Mediated miR-30a-5p Inhibition Enhances Proliferation and Inhibits Apoptosis in Colorectal Cancer Cells

1
Radiation Biology Research Center, Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital, Linkou 333, Taiwan
2
Division of Gastroenterology, Cheng Hsin General Hospital, Taipei 112, Taiwan
3
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 110, Taiwan
4
Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
*
Author to whom correspondence should be addressed.
Equal contribution.
Int. J. Mol. Sci. 2020, 21(19), 7315; https://doi.org/10.3390/ijms21197315
Received: 31 August 2020 / Revised: 30 September 2020 / Accepted: 1 October 2020 / Published: 3 October 2020
(This article belongs to the Special Issue Advances in Biological Functions of STAT3 2.0)
Signal transducer and activator of transcription 3 (STAT3), a transcriptional factor involved in tumorigenesis and cancer stemness formation, contributes to drug resistance in cancer therapies. STAT3 not only mediates gene transcription but also participates in microRNA suppression. This study identified a STAT3-downstream micro RNA (miRNA) involved in drug resistance against regorafenib in colorectal cancer stem-like tumorspheres. Small RNAseq was used to investigate differential microRNAs in colorectal cancer cell-derived tumorspheres and in a STAT3-knockdown strain. The miRNA-mediated genes were identified by comparing RNAseq data with gene targets predicted using TargetScan. Assays for detecting cell viability and apoptosis were used to validate findings. The formation of colorectal cancer stem-like tumorspheres was inhibited by BBI608, a STAT3 inhibitor, but not by regorafenib. Additional investigations for microRNA expression demonstrated an increase in 10 miRNAs and a decrease in 13 miRNAs in HT29-derived tumorspheres. A comparison of small RNAseq results between tumorspheres and HT29shSTAT3 cells revealed the presence of four STAT3-mediated miRNAs in HT29-derived tumorspheres: hsa-miR-215-5p, hsa-miR-4521, and hsa-miR-215-3p were upregulated, whereas miR-30a-5p was downregulated. Furthermore, hsa-miR-4521 was associated with poor overall survival probability, and miR-30a-5p was associated with better overall survival probability in patients with rectum cancer. Comparisons of RNAseq findings between HCT116- and HT29-derived tumorspheres revealed that HSPA5 were mediated by the STAT3-miR-30a-5p axis, which is overexpressed in colorectal tumorspheres associating to anti-apoptosis. In addition, the transfection of miR-30a-5p and inhibition of HSPA5 by HA15 significantly reduced cell viability and increased apoptosis in HT29 cells. In conclusion, a STAT3-miR-30a-5p-HSPA5 axis was observed against regorafenib-mediated apoptosis in colorectal cancer tumorspheres. The expression of miR-30a-5p was repressed by STAT3; in addition, HSPA5 was identified as the target gene of miR-30a-5p and contributed to both tumorsphere formation and anti-apoptosis. View Full-Text
Keywords: colorectal cancer; STAT3; miR-30a-5p; regorafenib; HSPA5 colorectal cancer; STAT3; miR-30a-5p; regorafenib; HSPA5
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MDPI and ACS Style

Cheng, C.-C.; Yang, B.-L.; Chen, W.-C.; Ho, A.-S.; Sie, Z.-L.; Lin, H.-C.; Chang, C.-C. STAT3 Mediated miR-30a-5p Inhibition Enhances Proliferation and Inhibits Apoptosis in Colorectal Cancer Cells. Int. J. Mol. Sci. 2020, 21, 7315. https://doi.org/10.3390/ijms21197315

AMA Style

Cheng C-C, Yang B-L, Chen W-C, Ho A-S, Sie Z-L, Lin H-C, Chang C-C. STAT3 Mediated miR-30a-5p Inhibition Enhances Proliferation and Inhibits Apoptosis in Colorectal Cancer Cells. International Journal of Molecular Sciences. 2020; 21(19):7315. https://doi.org/10.3390/ijms21197315

Chicago/Turabian Style

Cheng, Chun-Chia, Bi-Ling Yang, Wen-Chao Chen, Ai-Sheng Ho, Zong-Lin Sie, Hsin-Chi Lin, and Chun-Chao Chang. 2020. "STAT3 Mediated miR-30a-5p Inhibition Enhances Proliferation and Inhibits Apoptosis in Colorectal Cancer Cells" International Journal of Molecular Sciences 21, no. 19: 7315. https://doi.org/10.3390/ijms21197315

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