Abstract
Mitophagy is a conserved cellular process that plays a vital role in maintaining cellular homeostasis by selectively removing dysfunctional mitochondria. Notwithstanding that growing evidence suggests that mitophagy is implicated in pancreatic tumorigenesis, the effect of mitophagy-related genes on pancreatic cancer (PC) prognosis and therapeutic response remains largely unknown. In this study, we sought to construct a mitophagy-related gene signature and assessed its ability to predict the survival, immune activity, mutation status, and chemotherapy response of PC patients. During the screening process, we identified three mitophagy-related genes (PRKN, SRC, VDAC1) from The Cancer Genome Atlas (TCGA) cohort and a 3-gene signature was established. The prognostic model was validated using an International Cancer Genome Consortium (ICGC) cohort and two Gene Expression Omnibus (GEO) cohorts. According to the median risk score, PC patients were divided into high and low-risk groups, and the high-risk group correlated with worse survival in the four cohorts. The risk score was then identified as an independent prognostic predictor, and a predictive nomogram was constructed to guide clinical decision-making. Remarkably, enhanced immunosuppressive levels and higher mutation rates were observed in patients from the high-risk group, which may account for their poor survival. Furthermore, we found that high-risk patients were more sensitive to paclitaxel and erlotinib. In conclusion, a mitophagy-related gene signature is a novel prognostic model that can be used as a predictive indicator and allows prognostic stratification of PC patients.
Highlights
Pancreatic cancer (PC) is a devastating digestive tract malignancy accounting for 4.7% of cancer-related deaths, and could reportedly become the third leading cause of cancer death by 2025 (Sung et al, 2021)
The Protein-Protein Interaction (PPI) network was constructed to identify the interactions of these mitophagyrelated Differentially Expressed Genes (DEGs), and the results of PPI network analysis indicated that translocase of outer mitochondrial membrane 20 (TOMM20) was a hub gene (Figure 1D)
Mitophagy has a dual role in PC progression, which mainly depends on their clinical features, tumor microenvironment, and mutation status (Li et al, 2018; Humpton et al, 2019)
Summary
Pancreatic cancer (PC) is a devastating digestive tract malignancy accounting for 4.7% of cancer-related deaths, and could reportedly become the third leading cause of cancer death by 2025 (Sung et al, 2021). Most gene expression variations remain poorly characterized due to their complex molecular subtyping and tumor heterogeneity in PC patients, restraining their clinical translation (Hosein et al, 2020; Giuliani et al, 2021; Wang et al, 2021). Activated by hypoxia and metabolic stress, mitophagy enhances tumor cell survival by removing redundant mitochondria and reducing oxygen consumption (Vara-Perez et al, 2019). Mitophagy-related genes such as PINK1/PRKN and BNIP3L have been documented in pancreatic tumorigenesis (Humpton et al, 2019; Zhao et al, 2019), and are potential targets for PC treatment (Li et al, 2021). A comprehensive analysis of key modulator of mitophagy involved in PC progression and prognosis can guide clinical decision-making and provide more therapeutic options for PC patients
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