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.
Highlights
Pancreatic cancer is one of the most aggressive types of malignancies
By analyzing mitochondrial DNA (mtDNA) mutations in the primary tumors and metastases from six patients, the authors found that metastases have a higher number of mutations, suggesting that metastatic progression of pancreatic ductal adenocarcinoma (PDAC) may involve the accumulation of mtDNA mutations
High levels in the exosomes isolated from peripheral blood of PDAC patients.Elevated miR-21 levels correlate with shorter patients’ survival, both in the metastatic and adjuvant setting
Summary
Pancreatic cancer is one of the most aggressive types of malignancies. In the United States, the 5-year survival rate for people diagnosed with localized pancreatic cancer is 39%. Low ND4, COX1, and CYTB mRNA levels correlated with reduced overall survival in TSCC and in PDAC and other cancer types [32], suggesting that mitomiR levels may predict chemosensitivity and prognosis. MtDNA encodes proteins of the respiratory chain complexes; any pathogenic mutation affecting these proteins may potentially cause mitochondrial dysfunction and metabolic reprogramming, supporting cancer cell plasticity [33]. He et al [34] detected widespread heteroplasmic mtDNA variants in normal human cells and a significant increase in homoplasmic and heteroplasmic variants in colorectal cancer. In pancreatic cancer, there are still controversies about the prevalence and significance of mtDNA changes in cancer development and progression owing to the limited number of studies in this field
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