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

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.

SUBMITTER: Wang Q

PROVIDER: S-EPMC7019160 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Wang Qing Q Li Mengge M Gan Yu Y Jiang Shuheng S Qiao Jie J Zhang Wei W Fan Yingchao Y Shen Yuling Y Song Yanfang Y Meng Zihong Z Yao Ming M Gu Jianren J Zhang Zhigang Z Tu Hong H

Theranostics 20200112 5

<b>Purpose</b>: 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. <b>Experimental Design</b>: The expr ...[more]

PMID: 32089737

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and is projected to be the second most common cause of cancer-related death by 2030, with an overall 5-year survival rate between 7% and 9%. Despite recent advances in surgical, chemotherapy, and radiotherapy techniques, the outcome for patients with PDAC remains poor. Poor prognosis is multifactorial, including the likelihood of sub-clinical metastatic disease at presentation, late-stage at presentation, absence of early and reliable diagnostic biomarkers, and complex biology surrounding the extensive desmoplastic PDAC tumour micro-environment. Microbiota refers to all the microorganisms found in an environment, whereas microbiome is the collection of microbiota and their genome within an environment. These organisms reside on body surfaces and within mucosal layers, but are most abundantly found within the gut. The commensal microbiome resides in symbiosis in healthy individuals and contributes to nutritive, metabolic and immune-modulation to maintain normal health. Dysbiosis is the perturbation of the microbiome that can lead to a diseased state, including inflammatory bowel conditions and aetiology of cancer, such as colorectal and PDAC. Microbes have been linked to approximately 10% to 20% of human cancers, and they can induce carcinogenesis by affecting a number of the cancer hallmarks, such as promoting inflammation, avoiding immune destruction, and microbial metabolites can deregulate host genome stability preceding cancer development. Significant advances have been made in cancer treatment since the advent of immunotherapy. The microbiome signature has been linked to response to immunotherapy and survival in many solid tumours. However, progress with immunotherapy in PDAC has been challenging. Therefore, this review will focus on the available published evidence of the microbiome association with PDAC and explore its potential as a target for therapeutic manipulation.

Dataset Information

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

Publications

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

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