Gamma synuclein promotes cancer metastasis through the MKK3/6-p38MAPK cascade

Liu, Jieya; Shao, Ting; Zhang, Jin; Liu, Qianyi; Hua, Hui; Zhang, Hongying; Wang, Jiao; Luo, Ting; Shi, Yuenian Eric; Jiang, Yangfu

doi:10.7150/ijbs.69155

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Theranostics

International Journal of Medical Sciences

Nanotheranostics

Journal of Cancer

Journal of Genomics

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Int J Biol Sci 2022; 18(8):3167-3177. doi:10.7150/ijbs.69155 This issue Cite

Research Paper

Gamma synuclein promotes cancer metastasis through the MKK3/6-p38MAPK cascade

Jieya Liu^1*, Ting Shao^1,6*, Jin Zhang¹, Qianyi Liu¹, Hui Hua², Hongying Zhang¹, Jiao Wang³, Ting Luo⁴, Yuenian Eric Shi⁵, Yangfu Jiang^1✉

1. Laboratory of Oncogene, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
2. Laboratory of Stem Cell Biology, West China Hospital, Sichuan University. Chengdu, China
3. School of Basic Medicine, Chengdu University of Traditional Chinese Medicine. Chengdu, China
4. Cancer center, West China Hospital, Sichuan University. Chengdu, China
5. Chimigen Bio, Chengdu, China
6. Current address: BeiGene (Shanghai) Co., Ltd, Shanghai, China
^*These authors contributed equally to this work.

Citation:

Liu J, Shao T, Zhang J, Liu Q, Hua H, Zhang H, Wang J, Luo T, Shi YE, Jiang Y. Gamma synuclein promotes cancer metastasis through the MKK3/6-p38MAPK cascade. Int J Biol Sci 2022; 18(8):3167-3177. doi:10.7150/ijbs.69155. https://www.ijbs.com/v18p3167.htm

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Abstract

Gamma synuclein (SNCG) is a neuronal protein that is also aberrantly overexpressed in various types of human cancer. SNCG overexpression promotes cancer invasion and metastasis. However, the mechanisms that drive cancer metastasis upon SNCG expression remain elusive. Elucidation of the mechanisms underlying the promotion of cancer metastasis by SNCG may help discover therapeutic avenues for SNCG-overexpressed cancer. Here, we show that SNCG promotes transforming growth factor-β (TGF-β)-induced p38 mitogen-activated protein kinase (MAPK) phosphorylation. Mechanistically, SNCG promotes p38MAPK phosphorylation by interacting with the MAPK kinase 3/6 (MKK3/6) and prevents their degradation. SNCG knockdown leads to a decrease in TGF-β-induced phosphorylation of MKK3/6; and abrogates the induction of matrix metalloproteinase (MMP)-9 expression by TGF-β and its target gene Twist1. Furthermore, p38MAPK inhibition abrogates the promotion of MMP-9 expression and cancer cell invasion by SNCG. Both p38MAPK and MMP inhibitors can suppress the promotion of cancer cell invasion by SNCG. Finally, overexpression of SNCG in liver cancer cells promotes lung metastasis, which can be suppressed by the p38MAPK inhibitor. Together, our data uncover a previously unknown role of SNCG in promoting TGF-β-MKK3/6-p38MAPK signaling. This study highlights the critical role of p38MAPK in the promotion of cancer metastasis by SNCG, and indicates that p38MAPK inhibitor may serve as a potential therapeutic for SNCG-overexpressed cancer.

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APA

Liu, J., Shao, T., Zhang, J., Liu, Q., Hua, H., Zhang, H., Wang, J., Luo, T., Shi, Y.E., Jiang, Y. (2022). Gamma synuclein promotes cancer metastasis through the MKK3/6-p38MAPK cascade. International Journal of Biological Sciences, 18(8), 3167-3177. https://doi.org/10.7150/ijbs.69155.

ACS

Liu, J.; Shao, T.; Zhang, J.; Liu, Q.; Hua, H.; Zhang, H.; Wang, J.; Luo, T.; Shi, Y.E.; Jiang, Y. Gamma synuclein promotes cancer metastasis through the MKK3/6-p38MAPK cascade. Int. J. Biol. Sci. 2022, 18 (8), 3167-3177. DOI: 10.7150/ijbs.69155.

NLM

CSE

Liu J, Shao T, Zhang J, Liu Q, Hua H, Zhang H, Wang J, Luo T, Shi YE, Jiang Y. 2022. Gamma synuclein promotes cancer metastasis through the MKK3/6-p38MAPK cascade. Int J Biol Sci. 18(8):3167-3177.

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