Abstract
Simple SummaryA total of 10 genes (YWHAZ, F3, TMOD3, NFE2L3, ENDOD1, ITGA3, RRAS, PRSS23, TOP2A, and LRRFIP1) were identified as tumor suppressive miR-30c-5p and miR-30c-2-3p targets in pancreatic ductal adenocarcinoma (PDAC), and expression of these genes were independent prognostic factors for patient survival. Furthermore, aberrant expression of TOP2A and its transcriptional activators (SP1 and HMGB2) enhanced malignant transformation of PDAC cells.Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of cancer, and its prognosis is abysmal; only 25% of patients survive one year, and 5% live for five years. MicroRNA (miRNA) signature analysis of PDAC revealed that both strands of pre-miR-30c (miR-30c-5p, guide strand; miR-30c-2-3p, passenger strand) were significantly downregulated, suggesting they function as tumor-suppressors in PDAC cells. Ectopic expression assays demonstrated that these miRNAs attenuated the aggressiveness of PDAC cells, e.g., cell proliferation, migration, and invasiveness. Through a combination of in silico analyses and gene expression data, we identified 216 genes as putative oncogenic targets of miR-30c-5p and miR-30c-2-3p regulation in PDAC cells. Among these, the expression of 18 genes significantly predicted the 5-year survival rates of PDAC patients (p < 0.01). Importantly, the expression levels of 10 genes (YWHAZ, F3, TMOD3, NFE2L3, ENDOD1, ITGA3, RRAS, PRSS23, TOP2A, and LRRFIP1) were found to be independent prognostic factors for patient survival (p < 0.01). We focused on TOP2A (DNA Topoisomerase II Alpha) and investigated its potential as a therapeutic target for PDAC. The overexpression of TOP2A and its transcriptional activators (SP1 and HMGB2) was detected in PDAC clinical specimens. Moreover, the knockdown of TOP2A enhanced the sensitivity of PDAC cells to anticancer drugs. Our analyses of the PDAC miRNA signature and tumor-suppressive miRNAs provide important insights into the molecular pathogenesis of PDAC.
Highlights
Pancreatic ductal adenocarcinoma (PDAC), which accounts for the majority of pancreatic cancer, is one of the most malignant tumors in the world and the third leading cause of cancer death, characterized by frequent metastases and profound chemotherapy resistance [1,2].The 5-year relative survival rate for pancreatic cancer is the lowest among cancers—only 9% across all stages, and the death rates for pancreatic cancers have risen over the past decade [3]
Ectopic expression assays demonstrated that their expression attenuated the malignant phenotypes of PDAC cells and that the genes they regulate were aberrantly expressed in PDAC clinical specimens
We further investigated the clinical significance of TOP2A transcriptional regulators—HDAC1, HDAC2, HMGB1, HMGB2, NFYA, NFYB, NFYC, and Specific protein 1 (SP1)—in PDAC
Summary
Pancreatic ductal adenocarcinoma (PDAC), which accounts for the majority of pancreatic cancer (approximately 90%), is one of the most malignant tumors in the world and the third leading cause of cancer death, characterized by frequent metastases and profound chemotherapy resistance [1,2]. The 5-year relative survival rate for pancreatic cancer is the lowest among cancers—only 9% across all stages, and the death rates for pancreatic cancers have risen over the past decade [3]. To make matters worse, owing to the asymptomatic nature of the early stage of the disease and the absence of efficient diagnostic methods, most patients with PDAC present with the locally advanced and inoperable disease at diagnosis [3,4,5,6]. It is essential to search for new diagnostic markers and develop new therapeutic strategies based on the latest genomic analyses of PDAC.
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