Mitochondrial DNA and MitomiR Variations in Pancreatic Cancer: Potential Diagnostic and Prognostic Biomarkers

Abstract

Pancreatic cancer is an aggressive disease with poor prognosis. Only about 15–20% of patients diagnosed with pancreatic cancer can undergo surgical resection, while the remaining 80% are diagnosed with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). In these cases, chemotherapy and radiotherapy only confer marginal survival benefit. Recent progress has been made in understanding the pathobiology of pancreatic cancer, with a particular effort in discovering new diagnostic and prognostic biomarkers, novel therapeutic targets, and biomarkers that can predict response to chemo- and/or radiotherapy. Mitochondria have become a focus in pancreatic cancer research due to their roles as powerhouses of the cell, important subcellular biosynthetic factories, and crucial determinants of cell survival and response to chemotherapy. Changes in the mitochondrial genome (mtDNA) have been implicated in chemoresistance and metastatic progression in some cancer types. There is also growing evidence that changes in microRNAs that regulate the expression of mtDNA-encoded mitochondrial proteins (mitomiRs) or nuclear-encoded mitochondrial proteins (mitochondria-related miRs) could serve as diagnostic and prognostic cancer biomarkers. This review discusses the current knowledge on the clinical significance of changes of mtDNA, mitomiRs, and mitochondria-related miRs in pancreatic cancer and their potential role as predictors of cancer risk, as diagnostic and prognostic biomarkers, and as molecular targets for personalized cancer therapy.

Drug Resistance in Cancers: A Free Pass for Bullying

“…Reduced mtDNA also facilitated 5-FU and oxaliplatin resistance in CRC, in which aerobic glycolysis was induced and the AKT/mTOR signaling pathway was activated [ 189 ]. Consistently, mutations in mtDNA, especially trans-mitochondrial hybrids (cybrids) with mtDNA, are responsible for staurosporine, 5-FU, and CDDP resistance in pancreatic cancer [ 190 ]. Interestingly, mitochondrial transfer via exosome from fibroblasts to HeLa cells or SASr 0 cells with depleted mtDNA restored their proliferative capacity and sensitivity to CDDP, indicating that mitochondrial transfer can be considered a potential therapeutic strategy [ 191 ].…”

Mitochondrial related genome-wide Mendelian randomization identifies putatively causal genes for multiple cancer types

“… 4 Many experimental and epidemiological studies have attempted to infer the causal relationship between mitochondrial dysfunction and cancer by exploring the selective mitochondrial DNA (mtDNA) and mitochondrial-related nuclear DNA mutations that affect mitochondrial function and are associated with the risk of specific cancer types. 5 , 6 However, the results generated from those studies are inconsistent and one of the reasons is the methodologies used in these studies, which do not consider the effect of confounders to differentiate between cause and consequence. Therefore, a comprehensive analysis of all genes related to mitochondrial dysfunction in multiple cancer types by a robust method is required to determine whether mitochondrial dysfunction per se is a cause or consequence of cancer.…”

Preanalytical Variables in the Analysis of Mitochondrial DNA in Whole Blood and Plasma from Pancreatic Cancer Patients

“…Pancreatic cancer is an extremely malignant and aggressive disease with a limited prognosis and rising incidence, being responsible for an estimated 48,220 deaths in the United States in 2021 [ 1 ]. To-date the only curative therapy for pancreatic ductal adenocarcinomas (PDACs) is surgical resection; however, only 15–20% of patients with localized cancer can be cured, while the remaining ~80% have a poor prognosis due to locally advanced or metastasized disease at the time of diagnosis [ 2 , 3 ]. This underscores the importance of early diagnosis and timely treatment.…”

“…Tumor tissue has an altered energy uptake thus leading to the notion that any pathogenic mutations in mtDNA or copy number variations and further changes in energy production could act as a potential biomarker for several cancer types [ 28 ]. This is a consequence of changes in cellular metabolism, the inhibition of the respiratory chain, and the potential increase of reactive oxygen species (ROS) that could initiate tumor growth [ 5 ], chemoresistance, and supporting cancer cell plasticity [ 3 , 38 ]. The mtDNA copy number has been reported to vary between cancer and normal tissue cells.…”

“…Pancreatic cancer originates due to the accumulation of heterogenic, genetic, and epigenetic alterations, but there is also evidence that mutations in mtDNA could be associated with malignant transformation [ 27 , 39 , 40 , 41 , 42 , 43 ]. Due to a limited number of studies, however, results show different associations between mtDNA copy number and carcinogenesis, as well as no concrete proof that mtDNAcn decrease has an impact on overall survival in resectable PDACs [ 3 ].…”