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ARTICLE

miR-100-5p Enhances Cell Cycle-Mediated Chemoresistance by Modulating the CTDSPL/pRB/E2F1 Signaling Pathway in Oxaliplatin-Resistant Colorectal Cancer Cells

Yen-Pin Chen1,2,3, Rathinasamy Baskaran4, Hema Sri Devi4, Chaouhan Hitesh Singh4, Yu-Jung Lin4,5, Marthandam Asokan Shibu6, Wei-Wen Kuo7, Shih-Chieh Liao8, Ming-Cheng Chen9, Tso-Fu Wang10, Chi-Cheng Li11, Tsung-Jung Ho12, Tzu-Ching Shih13, Shinn-Zong Lin14,15,16,*, Chih-Yang Huang4,17,18,19,*
1 School of Medicine, National Defense Medical University, Taipei, Taiwan
2 Department of Orthopedic Surgery, Tri-Service General Hospital, Taipei, Taiwan
3 Department of Orthopedics, Taichung Armed Forces General Hospital, Taichung, Taiwan
4 Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
5 Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
6 Department of Biotechnology, Bharathiar University, Coimbatore, India
7 Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
8 Graduate Institute of Chinese Medical Science, China Medical University, 91 Hsueh-Shih Road, Taichung, Taiwan
9 Department of Surgery, Division of Colorectal Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
10 Department of Hematology and Oncology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
11 International Medical Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
12 Department of Chinese Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan
13 Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, Taiwan
14 Buddhist Tzu Chi Foundation Hospital, Hualien, Taiwan
15 Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
16 Department of Neurosurgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
17 Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
18 Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan
19 Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
* Corresponding Author: Shinn-Zong Lin. Email: email; Chih-Yang Huang. Email: email
(This article belongs to the Special Issue: Overcoming Drug Resistance in Cancer: Strategies and Natural Compound-Based Therapeutics)

Oncology Research https://doi.org/10.32604/or.2026.073080

Received 10 September 2025; Accepted 26 January 2026; Published online 19 February 2026

Abstract

Objective: MicroRNAs (miRNAs) are small, non-coding RNAs that play a key role in the development of chemoresistance in various cancer types, including colorectal cancer (CRC). In this study, we aimed to study the underlying mechanisms of miRNA in chemotherapy-resistant CRC. Methods: LoVo CRC cell line was exposed to oxaliplatin at an increased dose, and cells were cultured in the presence of oxaliplatin to develop LoVoOXR cells. Microarray and Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR), western blot, and transwell assay were used to evaluate the chemoresistance in LoVoOXR CRC cells. Results: Microarray and qRT-PCR analysis showed an increased expression of miR-100-5p in LoVoOXR cells. MTT assay and flow cytometry analysis revealed less apoptosis and higher cell viability in LoVoOXR cells. mRNA prediction target gene analysis showed C-terminal domain small phosphatase-like (CTDSPL), a phosphatase-like tumor suppressor, as a key target of miR-100-5p. CTDSPL expression was low in LoVoOXR cells compared to LoVoWT cells. miR-100-5p regulates G1/S and S-phase transitions and inhibits differentiation by targeting the CTDSPL/pRB/E2F1 signaling pathway, which involves the modulation of cell cycle effectors in LoVoOXR cells. Further, we found that forkhead box P3 (FOXP3), as the upstream target of miR-100-5p, is highly expressed in LoVoOXR cells. Inhibiting miR-100-5p and FOXP3 down-regulates miR-100-5p expression, while increased CTDSPL expression contributed to reduced cell proliferation and promoted cell apoptosis in LoVoOXR CRC cells. Conclusions: miR-100-5p plays an oncogenic role in inducing chemoresistance through modulation of the CTDSPL/retinoblastoma protein (pRB)/E2F transcription factor 1 (E2F1) axis in CRC cells.

Keywords

miR-100-5p; C-terminal domain small phosphatase-like (CTDSPL)/retinoblastoma protein (pRB)/E2F transcription factor 1 (E2F1); chemoresistance; cell cycle progression; colorectal cancers

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