2. Academic Validation
  3. IGF2BP3 regulates EMP1 stability in an m6A-dependent manner and activates the TGF-β pathway to promote pancreatic cancer invasion

IGF2BP3 regulates EMP1 stability in an m6A-dependent manner and activates the TGF-β pathway to promote pancreatic cancer invasion

  • Cell Death Dis. 2025 Nov 24;16(1):858. doi: 10.1038/s41419-025-08155-1.
Long Liu # 1 2,  Yu Zhang # 3 4,  Yuxi Huang # 5,  Xiaohong Zhao 6,  Hongxing Fu 1,  Lin Chen 7,  Qi Wang 3,  Xingyu Liu 1,  Xiang Zheng 1,  Hengqing Zhu 8,  Zheping Fang 9,  Zhenzhen Gao 10,  Sheng Yan 11
Affiliations

Affiliations

  • 1 Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88, Jiefang Road, Shangcheng District (Jiefang Road Hospital District), Hangzhou, Zhejiang Province, China.
  • 2 Department of Hepatobiliary and Pancreatic Surgery, Taizhou Hospital, Zhejiang University School of Medicine, China. No.150 Ximen Street, Linhai City, Taizhou City, Zhejiang Province, China.
  • 3 Department of Oncology, The First Affiliated Hospital of Anhui Medical University. 218 Jixi Road, Shushan District, Hefei City, Anhui Province, China.
  • 4 The First Hospital of the University of Science and Technology of China West District (Anhui Cancer Hospital). No. 107, East Huanhu Road, Shushan District, Hefei City, Anhui Province, China.
  • 5 Taizhou Hospital of Wenzhou Medical University. No.150 Ximen Street, Linhai City, Taizhou City, Zhejiang Province, China.
  • 6 School of Pharmacy, Hangzhou Normal University. No. 2318, Yuhangtang Road, Yuhang District, Hangzhou, Zhejiang Province, China.
  • 7 National University of Singapore School of Pharmacy. Block S4A, Level 3 18 Science Drive 4, Singapore, 117543, Singapore.
  • 8 Department of Thyroid Surgery, Second Affiliated Hospital School of Medicine, Zhejiang University, Hangzhou, China.
  • 9 Department of Hepatobiliary and Pancreatic Surgery, Taizhou Hospital, Zhejiang University School of Medicine, China. No.150 Ximen Street, Linhai City, Taizhou City, Zhejiang Province, China. [email protected].
  • 10 Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88, Jiefang Road, Shangcheng District (Jiefang Road Hospital District), Hangzhou, Zhejiang Province, China. [email protected].
  • 11 Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88, Jiefang Road, Shangcheng District (Jiefang Road Hospital District), Hangzhou, Zhejiang Province, China. [email protected].
  • # Contributed equally.
PMID: 41285728 DOI: 10.1038/s41419-025-08155-1
Abstract

Local invasion is considered a premonitor of tumor metastasis which cause curative difficulties and undesired prognosis in patients with Pancreatic ductal adenocarcinoma (PDAC). The importance of mRNA N6-methyladenosine (m6A) modification during tumor invasion is controversial as it plays distinct roles which mainly attributed to different m6A reader proteins exert function. In current study, the level of m6A expression in PDAC was analyzed by IHC and ELISA, all m6A-regulated genes in PDAC detected by qPCR. The downstream gene EMP1 was screened by analyzing IGF2BP3 knockdown RNA-seq, IGF2BP3-RIP, MeRIP-seq, and PDAC-survival related genes. And m6A modification sites of EMP1 RNA was verified by MeRIP-qPCR, RIP-qPCR, and dual luciferase assays. EMP1-binding protein VASP was identified by mass spectrometry. Cell migration and invasive activity were detected using cytoskeletal staining, scratch assay, transwell assay, subcutaneous tumor and lung metastasis models. Finally, prognosis and immune microenvironment was analyzed in PDAC by IHC and multiple immunofluorescence staining. This work shows that m6A reader IGF2BP3 is remarkably upregulated in local invasion PDAC and indicates worse prognosis of patients. Mechanistically, IGF2BP3 recognized m6A-modified EMP1 mRNAs to prolong stability of them, which inhibits the hindrance of SMAD7 to SMAD3/4 phosphorylation by promoting the binding of VASP and SMAD7. Finally, a tight correlation of the local invasion/IGF2BP3/EMP1 and infiltration of immune cells in the tumor microenvironment is evidenced in clinical PDAC. In conclusions, IGF2BP3 functions as an invasion driver that induces PDAC development via the EMP1/TGF-β axis. And IGF2BP3/EMP1 axis may be involved in regulating microenvironmental remodeling in pancreatic Cancer.

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