LAMB3 drives gastric cancer progression through SAMD4A-mediated degradation of PHLPP2 mRNA leading to sustained PI3K-Akt activation

  • Br J Cancer. 2026 Jun 17. doi: 10.1038/s41416-026-03496-w.
Jiamei Guo  #  1 ,  Fenglin Cai  #  2 ,  Mengmeng Zhang  #  3 ,  Xinyang Nie  #  1 ,  Mingzhi Cai  1 ,  Feiyu Meng  1 ,  Xingyu Li  1 ,  Zixiang Wei  1 ,  Yi Yang  4 ,  Rupeng Zhang  1 ,  Yikun Yao  5 ,  Yongzhan Nie  6 ,  Jingyu Deng  7  8
Affiliations
  • 1. Department of Gastric Surgery, Tianjin Medical University Cancer Institute & Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin Key Laboratory of Digestive Cancer; Tianjin's Clinical Research Center for Cancer, Tianjin, China.
  • 2. Department of Oncology, The First Affiliated Hospital with Nanjing Medical University, The First Clinical Medical College of Nanjing Medical University, Nanjing Medical University, Nanjing, China.
  • 3. Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
  • 4. Department of Hepatobiliary Surgery, State Key Laboratory of Molecular Oncology, Beijing Key Laboratory of Cell and Gene Therapy for Digestive System Tumor, Key Laboratory of Gene Editing Screening and Research and Development of Digestive System Tumor Drugs (CAMS), National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 5. Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
  • 6. State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China. [email protected].
  • 7. Department of Gastric Surgery, Tianjin Medical University Cancer Institute & Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin Key Laboratory of Digestive Cancer; Tianjin's Clinical Research Center for Cancer, Tianjin, China. [email protected].
  • 8. Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking UnionMedical College, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 42310093 DOI: 10.1038/s41416-026-03496-w
Abstract

Background: Laminin subunit beta 3 (LAMB3) overexpression has been implicated in Cancer progression, but its molecular role in gastric Cancer (GC) remains unclear. This study aimed to elucidate how LAMB3 promotes GC malignancy and identify the underlying signalling pathways.

Methods: The clinical significance of LAMB3 was analysed by bioinformatics and immunohistochemistry (IHC) on tissue microarrays. Correlations with clinicopathological parameters were evaluated using Chi-square or Fisher's exact tests, and prognostic value was assessed by log-rank and multivariate COX regression analyses. Functional assays, including CCK-8, colony formation, Transwell, and xenograft models, were performed to examine the roles of LAMB3 and its downstream effector. Mechanistic studies involved RNA Sequencing (RNA-seq), gain- and loss-of-function experiments, RT-qPCR, RNA immunoprecipitation, and western blotting.

Results: LAMB3 was significantly upregulated in GC and correlated with aggressive features and poor prognosis. LAMB3 enhanced GC cell proliferation, migration, and invasion. RNA-seq identified sterile alpha motif domain-containing protein 4 A (SAMD4A) as a critical downstream effector. Silencing SAMD4A suppressed, while its restoration rescued, LAMB3-induced malignancy. Mechanistically, LAMB3 activated PI3K-Akt signalling through SAMD4A-mediated degradation of PHLPP2 mRNA.

Conclusions: This study uncovers a previously unrecognised LAMB3-SAMD4A-PHLPP2 regulatory axis that sustains PI3K-Akt activation and drives GC progression, offering potential prognostic and therapeutic value.

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