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

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.

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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. Available from https://www.thno.org/v11p3196.htm

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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