Theranostics 2020; 10(5):2141-2157. doi:10.7150/thno.38704 This issue Cite

Research Paper

Mitochondrial Protein UQCRC1 is Oncogenic and a Potential Therapeutic Target for Pancreatic Cancer

Qing Wang1*, Mengge Li1*, Yu Gan1, Shuheng Jiang1, Jie Qiao1, Wei Zhang1, Yingchao Fan1, Yuling Shen1,2, Yanfang Song1, Zihong Meng1, Ming Yao1, Jianren Gu1, Zhigang Zhang1, Hong Tu1✉

1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
2. Department of Head and Neck Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
*These authors contributed equally

Citation:
Wang Q, Li M, Gan Y, Jiang S, Qiao J, Zhang W, Fan Y, Shen Y, Song Y, Meng Z, Yao M, Gu J, Zhang Z, Tu H. Mitochondrial Protein UQCRC1 is Oncogenic and a Potential Therapeutic Target for Pancreatic Cancer. Theranostics 2020; 10(5):2141-2157. doi:10.7150/thno.38704. https://www.thno.org/v10p2141.htm
Other styles

File import instruction

Abstract

Graphic abstract

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a malignant disease with a poor prognosis. One prominent aspect of PDAC that contributes to its aggressive behavior is its altered cellular metabolism. The aim of this study was to characterize the oncogenic effects of ubiquinol-cytochrome c reductase core protein I (UQCRC1), a key component of mitochondrial complex III, in PDAC development and to assess its potential as a therapeutic target for PDAC.

Experimental Design: The expression of UQCRC1 in human PDAC tissues and p48-Cre/p53Flox/WT/LSL-KrasG12D (KPC) mouse pancreatic intraepithelial neoplasias (PanINs) was determined by immunohistochemistry. The role of UQCRC1 in promoting PDAC growth was evaluated in vitro in PANC-1 and CFPAC-1 cells and in vivo in transplanted mouse models of PDAC. Extracellular flux and RNA-Seq analyses were applied to investigate the mechanism of UQCRC1 in the regulation of mitochondrial metabolism and PDAC cell growth. The therapeutic potential of UQCRC1 in PDAC was assessed by knockdown of UQCRC1 using an RNA interference approach.

Results: UQCRC1 expression showed a gradual increase during the progression from PanIN stages to PDAC in KPC mice. Elevated expression of UQCRC1 was observed in 72.3% of PDAC cases and was correlated with poor prognosis of the disease. UQCRC1 promoted PDAC cell growth in both in vitro experiments and in vivo subcutaneous and orthotopic mouse models. UQCRC1 overexpression resulted in increased mitochondrial oxidative phosphorylation (OXPHOS) and ATP production. The overproduced ATP was released into the extracellular space via the pannexin 1 channel and then functioned as an autocrine or paracrine agent to promote cell proliferation through the ATP/P2Y2-RTK/AKT axis. UQCRC1 knockdown or ATP release blockage could effectively inhibit PDAC growth.

Conclusion: UQCRC1 has a protumor function and may serve as a potential prognostic marker and therapeutic target for PDAC.

Keywords: Pancreatic Ductal Adenocarcinoma, UQCRC1, Mitochondrial Oxidative Phosphorylation, Extracellular ATP


Citation styles

APA
Wang, Q., Li, M., Gan, Y., Jiang, S., Qiao, J., Zhang, W., Fan, Y., Shen, Y., Song, Y., Meng, Z., Yao, M., Gu, J., Zhang, Z., Tu, H. (2020). Mitochondrial Protein UQCRC1 is Oncogenic and a Potential Therapeutic Target for Pancreatic Cancer. Theranostics, 10(5), 2141-2157. https://doi.org/10.7150/thno.38704.

ACS
Wang, Q.; Li, M.; Gan, Y.; Jiang, S.; Qiao, J.; Zhang, W.; Fan, Y.; Shen, Y.; Song, Y.; Meng, Z.; Yao, M.; Gu, J.; Zhang, Z.; Tu, H. Mitochondrial Protein UQCRC1 is Oncogenic and a Potential Therapeutic Target for Pancreatic Cancer. Theranostics 2020, 10 (5), 2141-2157. DOI: 10.7150/thno.38704.

NLM
Wang Q, Li M, Gan Y, Jiang S, Qiao J, Zhang W, Fan Y, Shen Y, Song Y, Meng Z, Yao M, Gu J, Zhang Z, Tu H. Mitochondrial Protein UQCRC1 is Oncogenic and a Potential Therapeutic Target for Pancreatic Cancer. Theranostics 2020; 10(5):2141-2157. doi:10.7150/thno.38704. https://www.thno.org/v10p2141.htm

CSE
Wang Q, Li M, Gan Y, Jiang S, Qiao J, Zhang W, Fan Y, Shen Y, Song Y, Meng Z, Yao M, Gu J, Zhang Z, Tu H. 2020. Mitochondrial Protein UQCRC1 is Oncogenic and a Potential Therapeutic Target for Pancreatic Cancer. Theranostics. 10(5):2141-2157.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.