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Rab31 promotes metastasis and cisplatin resistance in stomach adenocarcinoma through Twist1-mediated EMT.
- Source :
-
Cell death & disease [Cell Death Dis] 2023 Feb 13; Vol. 14 (2), pp. 115. Date of Electronic Publication: 2023 Feb 13. - Publication Year :
- 2023
-
Abstract
- Stomach adenocarcinoma (STAD) is one of the leading causes of cancer-related death globally. Metastasis and drug resistance are two major causes of failures in current chemotherapy. Here, we found that the expression of Ras-related protein 31 (Rab31) is upregulated in human STAD tissues and high expression of Rab31 is closely associated with poor survival time. Furthermore, we revealed that Rab31 promotes cisplatin resistance and metastasis in human STAD cells. Reduced Rab31 expression induces tumor cell apoptosis and increases cisplatin sensitivity in STAD cells; Rab31 overexpression yielded the opposite result. Rab31 silencing prevented STAD cell migration, whereas the overexpression of Rab31 increased the metastatic potential. Further work showed that Rab31 mediates cisplatin resistance and metastasis via epithelial-mesenchymal transition (EMT) pathway. In addition, we found that both Rab31 overexpression and cisplatin treatment results in increased Twist1 expression. Depletion of Twist1 enhances sensitivity to cisplatin in STAD cells, which cannot be fully reversed by Rab31 overexpression. Rab31 could activate Twist1 by activating Stat3 and inhibiting Mucin 1 (MUC-1). The present study also demonstrates that Rab31 knockdown inhibited tumor growth in mice STAD models. These findings indicate that Rab31 is a novel and promising biomarker and potential therapeutic target for diagnosis, treatment and prognosis prediction in STAD patients. Our data not only identifies a novel Rab31/Stat3/MUC-1/Twist1/EMT pathway in STAD metastasis and drug resistance, but it also provides direction for the exploration of novel strategies to predict and treat STAD in the future.<br /> (© 2023. The Author(s).)
- Subjects :
- Animals
Mice
Humans
Cisplatin pharmacology
Cisplatin therapeutic use
Cisplatin metabolism
Epithelial-Mesenchymal Transition genetics
Cell Line, Tumor
Twist-Related Protein 1 genetics
Twist-Related Protein 1 metabolism
Gene Expression Regulation, Neoplastic
Nuclear Proteins genetics
Nuclear Proteins metabolism
rab GTP-Binding Proteins genetics
rab GTP-Binding Proteins metabolism
Adenocarcinoma drug therapy
Adenocarcinoma genetics
Stomach Neoplasms drug therapy
Stomach Neoplasms genetics
Stomach Neoplasms metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 14
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 36781842
- Full Text :
- https://doi.org/10.1038/s41419-023-05596-4