Abstract A30: Differential processing of let 7a precursors influences gemcitabine chemosensitivity in pancreatic cancer: Role of ribonucleotide reductase subunit M2.

Abstract

Ribonucleotide reductase subunit M2 (RRM2) involved in deoxyribonucleotide synthesis acts as a key determinant of chemoresistance to nucleoside drugs (e.g., gemcitabine) used in treating pancreatic cancer. While silencing RRM2 expression by synthetic means (e.g., siRNA) improves the chemosensitivity of pancreatic cancer cells to gemcitabine, targeting endogenous molecules to advance gemcitabine chemotherapeutic responses has never been explored. Based on existing evidence and computational predictions, we hypothesized that the let-7 tumor suppressor microRNAs will inhibit RRM2-mediated gemcitabine chemoresistance in pancreatic cancer. Reduced expression of the majority of let-7 miRNAs with an inverse relationship to RRM2 expression was identified in inherently gemcitabine-resistant pancreatic cancer cells. Direct binding of let-7 miRNA to the 3’-UTR of RRM2 transcripts identified post-transcriptional repression of RRM2 as a novel phenomenon influencing gemcitabine chemosensitivity. Intriguingly, overexpression of human precursor-let-7 miRNAs led to differential RRM2 expression and gemcitabine chemosensitization in a poorly differentiated gemcitabine-resistant pancreatic cancer cell line MIA PaCa-2. Defective processing of the let-7a precursors to mature forms explained, in part, the discrepancies observed with let-7a expressional outcomes. Screening putative regulators of let-7a biogenesis in MIA PaCa-2 cells identified LIN-28 and SET oncoprotein to differentially modulate let-7 biogenesis and chemosensitivity in gemcitabinesensitive versus-resistant pancreatic cancer cells. Additionally, acquired gemcitabine chemoresistance was found to be less dependent on let-7 alterations. These data demonstrate an intricate post-transcriptional regulation of RRM2 expression by let-7 and that the manipulation of let-7 processing machinery may provide a mechanism for improving gemcitabine chemosensitivity in innately-resistant pancreatic cancer cells. Citation Format: Yangzom Bhutia, Sau Hung, Michael Thomson, Rajgopal Govindarajan. Differential processing of let 7a precursors influences gemcitabine chemosensitivity in pancreatic cancer: Role of ribonucleotide reductase subunit M2. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr A30.