2. Academic Validation
  3. LAD1 promotes malignant progression by diminishing ubiquitin-dependent degradation of vimentin in gastric cancer

LAD1 promotes malignant progression by diminishing ubiquitin-dependent degradation of vimentin in gastric cancer

  • J Transl Med. 2023 Sep 17;21(1):632. doi: 10.1186/s12967-023-04401-2.
Yingming Jiang # 1 2 3 4,  Yanchun Feng # 3 5 4,  Jintuan Huang # 2 3 4,  Zhenze Huang # 2 3 4,  Rongchang Tan 2 3 4,  Tuoyang Li 2 3 4,  Zijian Chen 2 3 4,  Xiaocheng Tang 2 3 4,  Jun Qiu 2 3 4,  Chujun Li 6 7 8,  Hao Chen 9 10 11,  Zuli Yang 12 13 14
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Endoscopy, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 510655, Guangzhou, China.
  • 2 Department of Gastric Surgery Section 2, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 510655, Guangzhou, China.
  • 3 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China.
  • 4 Department of Thyroid Hernia Surgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, Guangdong, China.
  • 5 Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-Sen University, 510655, Guangzhou, China.
  • 6 Department of Gastrointestinal Endoscopy, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 510655, Guangzhou, China. lichujun@mail.sysu.edu.cn.
  • 7 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China. lichujun@mail.sysu.edu.cn.
  • 8 Department of Thyroid Hernia Surgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, Guangdong, China. lichujun@mail.sysu.edu.cn.
  • 9 Department of Gastric Surgery Section 2, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 510655, Guangzhou, China. chenhao29@mail.sysu.edu.cn.
  • 10 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China. chenhao29@mail.sysu.edu.cn.
  • 11 Department of Thyroid Hernia Surgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, Guangdong, China. chenhao29@mail.sysu.edu.cn.
  • 12 Department of Gastric Surgery Section 2, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, 510655, Guangzhou, China. yangzuli@mail.sysu.edu.cn.
  • 13 Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510655, China. yangzuli@mail.sysu.edu.cn.
  • 14 Department of Thyroid Hernia Surgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, Guangdong, China. yangzuli@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 37718450 DOI: 10.1186/s12967-023-04401-2
Abstract

Background: Ladinin-1 (LAD1), an anchoring filament protein, has been associated with several Cancer types, including cancers of the colon, lungs, and breast. However, it is still unclear how and why LAD1 causes gastric Cancer (GC).

Methods: Multiple in vitro and in vivo, functional gains and loss experiments were carried out in the current study to confirm the function of LAD1. Mass spectrometry was used to find the proteins that interact with LAD1. Immunoprecipitation analyses revealed the mechanism of LAD1 involved in promoting aggressiveness.

Results: The results revealed that the LAD1 was overexpressed in GC tissues, and participants with increased LAD1 expression exhibited poorer disease-free survival (DFS) and overall survival (OS). Functionally, LAD1 promotes cellular invasion, migration, proliferation, and chemoresistance in vivo and in vitro in the subcutaneous patient-and cell-derived xenograft (PDX and CDX) tumor models. Mechanistically, LAD1 competitively bound to Vimentin, preventing it from interacting with the E3 ubiquitin Ligase macrophage erythroblast attacher (MAEA), which led to a reduction in K48-linked ubiquitination of Vimentin and an increase in Vimentin protein levels in GC cells.

Conclusions: In conclusion, the current investigation indicated that LAD1 has been predicted as a possible prognostic biomarker and therapeutic target for GC due to its ability to suppress Vimentin-MAEA interaction.

Keywords

Gastric cancer; LAD1; MAEA; Ubiquitination; Vimentin.

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