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Theranostics 2021; 11(7):3196-3212. doi:10.7150/thno.51976 This issue Cite

Research Paper

Metallothionein-1G suppresses pancreatic cancer cell stemness by limiting activin A secretion via NF-κB inhibition

Kai Li1, Zhicheng Zhang2, Yu Mei1, Qingzhu Yang1, Shupei Qiao1, Cheng Ni1, Yao Yao1, Xinyuan Li1, Mengmeng Li1, Dongdong Wei1, Wangjun Fu1, Xuefei Guo1, Xuemei Huang1, Huanjie Yang1,✉

1. School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China.
2. Department of General Surgery, Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.

✉ Corresponding author: E-mail: yanghjedu.cn

Citation:
Li K, Zhang Z, Mei Y, Yang Q, Qiao S, Ni C, Yao Y, Li X, Li M, Wei D, Fu W, Guo X, Huang X, Yang H. Metallothionein-1G suppresses pancreatic cancer cell stemness by limiting activin A secretion via NF-κB inhibition. Theranostics 2021; 11(7):3196-3212. doi:10.7150/thno.51976. https://www.thno.org/v11p3196.htm
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Abstract

Graphic abstract

Resistance to chemotherapy is a long-standing problem in the management of cancer, and cancer stem cells are regarded as the main source of this resistance. This study aimed to investigate metallothionein (MT)-1G involvement in the regulation of cancer stemness and provide a strategy to overcome chemoresistance in pancreatic ductal adenocarcinoma (PDAC).

Methods: MT1G was identified as a critical factor related with gemcitabine resistance in PDAC cells by mRNA microarray. Its effects on PDAC stemness were evaluated through sphere formation and tumorigenicity. LC-MS/MS analysis of conditional medium revealed that activin A, a NF-κB target, was a major protein secreted from gemcitabine resistant PDAC cells. Both loss-of-function and gain-of-function approaches were used to validate that MT1G inhibited NF-κB-activin A pathway. Orthotopic pancreatic tumor model was employed to explore the effects on gemcitabine resistance with recombinant follistatin to block activin A.

Results: Downregulation of MT1G due to hypermethylation of its promoter is related with pancreatic cancer stemness. Secretome analysis revealed that activin A, a NF-κB target, was highly secreted by drug resistant cells. It promotes pancreatic cancer stemness in Smad4-dependent or independent manners. Mechanistically, MT1G negatively regulates NF-κB signaling and promotes the degradation of NF-κB p65 subunit by enhancing the expression of E3 ligase TRAF7. Blockade of activin A signaling with follistatin could overcome gemcitabine resistance.

Conclusions: MT1G suppresses PDAC stemness by limiting activin A secretion via NF-κB inhibition. The blockade of the activin A signaling with follistatin may provide a promising therapeutic strategy for overcoming gemcitabine resistance in PDAC.

Keywords: MT1G, PDAC stemness, gemcitabine resistance, activin A, follistatin

Citation styles

APA
Li, K., Zhang, Z., Mei, Y., Yang, Q., Qiao, S., Ni, C., Yao, Y., Li, X., Li, M., Wei, D., Fu, W., Guo, X., Huang, X., Yang, H. (2021). Metallothionein-1G suppresses pancreatic cancer cell stemness by limiting activin A secretion via NF-κB inhibition. Theranostics, 11(7), 3196-3212. https://doi.org/10.7150/thno.51976.

ACS
Li, K.; Zhang, Z.; Mei, Y.; Yang, Q.; Qiao, S.; Ni, C.; Yao, Y.; Li, X.; Li, M.; Wei, D.; Fu, W.; Guo, X.; Huang, X.; Yang, H. Metallothionein-1G suppresses pancreatic cancer cell stemness by limiting activin A secretion via NF-κB inhibition. Theranostics 2021, 11 (7), 3196-3212. DOI: 10.7150/thno.51976.

NLM
Li K, Zhang Z, Mei Y, Yang Q, Qiao S, Ni C, Yao Y, Li X, Li M, Wei D, Fu W, Guo X, Huang X, Yang H. Metallothionein-1G suppresses pancreatic cancer cell stemness by limiting activin A secretion via NF-κB inhibition. Theranostics 2021; 11(7):3196-3212. doi:10.7150/thno.51976. https://www.thno.org/v11p3196.htm

CSE
Li K, Zhang Z, Mei Y, Yang Q, Qiao S, Ni C, Yao Y, Li X, Li M, Wei D, Fu W, Guo X, Huang X, Yang H. 2021. Metallothionein-1G suppresses pancreatic cancer cell stemness by limiting activin A secretion via NF-κB inhibition. Theranostics. 11(7):3196-3212.

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