Dissecting the METTL3/STC2 axis in colorectal cancer - implications for drug resistance and metastasis

Sep 23, 2026

Recent years have highlighted epigenetic modifications as key contributors to cancer development, with N6-methyladenosine (m6A) receiving particular attention. This study investigates m6A involvement in colorectal cancer by defining how METTL3 regulates STC2 expression and how this pathway influences cell proliferation, drug resistance to 5-fluorouracil (5-FU), and metastatic behavior. MeRIP-seq, mRNA-seq, EdU staining, CCK-8, Transwell, Western blot, and flow cytometry demonstrate METTL3–STC2 signaling promotes resistance and metastasis via ERS and oxidative stress, and modulates KRAS G12/G13 mutations. Overall, the work supports the METTL3/STC2 axis as a therapeutic target to counter drug resistance and metastasis.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages20

Reading Time50 min

AccessFree to download

Introduction

Colorectal cancer background and clinical challenges

Chemotherapy, 5-FU resistance, and KRAS mutations

m6A modification and its regulators

Mechanistic focus: METTL3/STC2 axis

Effects on STC2 expression and advanced CRC phenotypes

Links to ERS, oxidative stress, and KRAS G12/G13 mutations

Cell Biol Toxicol (2025) 41:100 [https://doi.org/10.1007/s10565-025-10043-5](https://doi.org/10.1007/s10565-025-10043-5) Dissecting the METTL3/STC2 axis in colorectal cancer: implications for drug resistance and metastasis Qiang Su · Kaiyue Wang · Ruohan Liao · Hanyu Zhang · Bochu Wang Received: 4 November 2024 / Accepted: 9 May 2025 © The Author(s) 2025 Abstract In recent years, the role of epigenetic modifications, especially N6-methyladenosine (m6A) modifications, in the occurrence and development of cancer has received increasing attention. This study aims to elucidate the role of m6A modification in colorectal cancer (CRC), focusing on the effect of METTL3 on STC2 expression and its effects on cell proliferation, drug resistance and metastasis. Using MeRIP-seq, mRNA-seq, EdU staining, CCK-8 (Cell Counting Kit-8) assay, Transwell assay, Western blot and flow cytometry, this study confirmed that RNA | Highlights
1. METTL3-mediated m6A modification upregulates STC2 expression in colorectal cancer.
2. The METTL3/STC2 axis promotes 5-FU resistance and metastasis via ERS and oxidative stress.
3. Increased STC2 facilitates KRAS G12/G13 mutations, contributing to drug resistance and fueling CRC progression | | --- | | Supplementary Information The online version contains supplementary material available at [https://doi](https://doi). org/10.1007/s10565-025-10043-5. | Q. Su · B. Wang (*) Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China [e-mail: wangbc@cqu.edu.cn](e-mail: wangbc@cqu.edu.cn) [Q. Su](Q. Su) · [H. Zhang](H. Zhang) Department of Pharmacy, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan, China methylation was predominantly located in the CDS region and that STC2 was overexpressed in advanced cancer and 5-FU (5-Fluorouracil)-resistant cell lines. Knockdown of STC2 increased the sensitivity of cells to 5-FU, reduced cell proliferation and metastatic capacity, and indicated that METTL3 positively regulates STC2 m6A modification. Further experiments showed that METTL3 knockdown reduced the IC50 (Half Maximal Inhibitory Concentration) of 5-FUresistant CRC cells, inhibited cell proliferation, ERS (Endoplasmic Reticulum Stress) and oxidative stress, and reduced KRAS G12 and G13 mutations, and these effects were reversed by STC2 overexpression. In vivo, METTL3 knockdown enhanced the efficacy of 5-FU and inhibited tumor metastasis, whereas STC2 overexpression counterbalanced these benefits. Overall, our findings suggest the METTL3/STC2 axis as a promising therapeutic target to combat drug resistance and metastasis in colorectal cancer. Keywords METTL3 · STC2 · M6 A modification · Colorectal cancer · Drug resistance K. Wang · R. Liao School of Pharmacy, North Sichuan Medical College, Nanchong, Sichuan, China H. Zhang Nanchong Key Laboratory of Individualized Drug Therapy, Nanchong, Sichuan, China Introduction Colorectal cancer (CRC) is a malignant tumor that occurs in the colon and rectum, which are the main components of the large intestine (Yuan et al. 2025a, b) . CRC has multiple etiologies, including poor lifestyle, environment, diet, and genetics (e.g., adenoma, inflammatory bowel disease, etc.) (Yuan et al. 2025a, b) . Besides, various chemicals, parasites and chronic gastrointestinal diseases are also potential triggers for the development of CRC (Mauri et al. 2025) . Based on the accumulation of multiple oncogene/oncogene mutations, colorectal cell deterioration results from multiple steps of interaction (Zhou, Zhang et al. 2024) . Due to the lack of early symptoms and detection markers, CRC is often diagnosed at an advanced stage, limiting curative treatment options like surgery (Mauri et al. 2025) . Therefore, there is an urgent need to investigate the therapeutic mechanisms of CRC. Chemotherapy is the key t

FAQs

What is the main purpose of this study on colorectal cancer?

To clarify how m6A modification contributes to colorectal cancer, specifically examining the role of METTL3 in regulating STC2 expression and how this affects proliferation, drug resistance, and metastasis.

Which experimental approaches were used to evaluate METTL3/STC2 effects?

The study used MeRIP-seq and mRNA-seq for RNA/m6A profiling, EdU staining and CCK-8 for proliferation, Transwell for metastasis, Western blot for protein analysis, and flow cytometry for related cellular measures.

How does the METTL3/STC2 axis influence drug resistance and metastasis?

The highlights indicate that the METTL3/STC2 axis promotes 5-FU resistance and metastasis via ERS and oxidative stress, while increased STC2 facilitates KRAS G12/G13 mutations that contribute to drug resistance and CRC progression.

Sep 23, 2026

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