2. Academic Validation
  3. MKRN1 promotes colorectal cancer metastasis by activating the TGF-β signalling pathway through SNIP1 protein degradation

MKRN1 promotes colorectal cancer metastasis by activating the TGF-β signalling pathway through SNIP1 protein degradation

  • J Exp Clin Cancer Res. 2023 Aug 24;42(1):219. doi: 10.1186/s13046-023-02788-w.
Yi Zhang # 1 2,  Qin-Shan Li # 3 4,  Hong-Lin Liu # 5,  Hong-Ting Tang 2,  Han-Lin Yang 2,  Dao-Qiu Wu 2,  Yu-Ying Huang 2,  Li-Cheng Li 6 7,  Li-Hong Liu 8,  Meng-Xing Li 9 10 11
Affiliations

Affiliations

  • 1 Guizhou Prenatal Diagnosis Center, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, Guizhou, People's Republic of China.
  • 2 Department of Clinical Biochemistry, School of Medical Laboratory Science, Guizhou Medical University, Guizhou, Guiyang, 550004, People's Republic of China.
  • 3 Guizhou Prenatal Diagnosis Center, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, Guizhou, People's Republic of China. liqinshan@gmc.edu.cn.
  • 4 Department of Clinical Biochemistry, School of Medical Laboratory Science, Guizhou Medical University, Guizhou, Guiyang, 550004, People's Republic of China. liqinshan@gmc.edu.cn.
  • 5 Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing, 100000, People's Republic of China.
  • 6 Clinical Medical College, Guizhou Medical University, Guizhou, Guiyang, 550004, People's Republic of China.
  • 7 Department of HematologyGuizhou Province Laboratory of Hematopoietic Stem Cell Transplantation Centre, Affiliated Hospital of Guizhou Medical University, Guizhou Province Institute of Hematology, Guizhou, Guiyang, People's Republic of China.
  • 8 Department of Pharmacy, China-Japan Friendship Hospital, Beijing, 100029, People's Republic of China. llh-hong@outlook.com.
  • 9 Clinical Medical College, Guizhou Medical University, Guizhou, Guiyang, 550004, People's Republic of China. lmx1234@gmc.edu.cn.
  • 10 Department of HematologyGuizhou Province Laboratory of Hematopoietic Stem Cell Transplantation Centre, Affiliated Hospital of Guizhou Medical University, Guizhou Province Institute of Hematology, Guizhou, Guiyang, People's Republic of China. lmx1234@gmc.edu.cn.
  • 11 Department of Pathophysiology, Guizhou Medical University, Guizhou, Guiyang, 550004, People's Republic of China. lmx1234@gmc.edu.cn.
  • # Contributed equally.
PMID: 37620897 DOI: 10.1186/s13046-023-02788-w
Abstract

Background: The Makorin ring finger protein 1 (MKRN1) gene, also called RNF61, is located on the long arm of chromosome 7 and is a member of the RING finger protein family. The E3 ubiquitin Ligase MKRN1 is closely linked to tumour development, but the exact mechanism needs to be elucidated. In this study, we aimed to investigate the specific mechanism and role of MKRN1 in colorectal Cancer (CRC) development.

Methods: MKRN1 expression in CRC was analysed using the Cancer Cell Line Encyclopaedia and the Cancer Genome Atlas (TCGA) databases. Rectal tumour tissues were frozen to explore the MKRN1 expression in CRC and its clinical significance. The impact of MKRN1 on CRC cell proliferation and migration was observed using CCK8, colony formation, wound healing, and transwell assays. A combination of MKRN1 quantitative proteomics, ubiquitination modification omics analysis, and a string of in vitro and in vivo experiments revealed the potential mechanisms by which MKRN1 regulates CRC metastasis.

Results: MKRN1 expression was significantly elevated in CRC tissues compared to paracancerous tissues and was positively linked with prognosis (P < 0.01). MKRN1 downregulation inhibits CRC cell proliferation, migration, and invasion. Conversely, MKRN1 overexpression promotes the proliferation, migration, and invasion of CRC cells. Mechanistically, MKRN1 induces epithelial-mesenchymal transition (EMT) in CRC cells via ubiquitination and degradation of Smad nuclear-interacting protein 1 (SNIP1). Furthermore, SNIP1 inhibits Transforming Growth Factor-β (TGF-β) signalling, and MKRN1 promotes TGF-β signalling by degrading SNIP1 to induce EMT in CRC cells. Finally, using conditional knockout mice, intestinal lesions and metastatic liver microlesions were greatly reduced in the intestinal knockout MKRN1 group compared to that in the control group.

Conclusions: High MKRN1 levels promote TGF-β signalling through ubiquitination and degradation of SNIP1, thereby facilitating CRC metastasis, and supporting MKRN1 as a CRC pro-cancer factor. The MKRN1/SNIP1/TGF-β axis may be a potential therapeutic target in CRC.

Keywords

Colorectal cancer; KRN1; Metastasis; SNIP1; TGF-β signalling.

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