miR-802 Suppresses Acinar-to-Ductal Reprogramming During Early Pancreatitis and Pancreatic Carcinogenesis

Abstract

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor that is almost uniformly lethal in humans. Activating mutations of KRAS are found in >90% of human PDACs and are sufficient to promote acinar-toductal metaplasia (ADM) during tumor initiation. The roles of miRNAs in oncogenic Kras-induced ADM are incompletely understood. METHODS: The Ptf1a Cre/þ LSL-Kras G12D/þ and Ptf1a Cre/þ LSL-Kras G12D/þ LSL-p53R172H/ þ and caeruleininduced acute pancreatitis mice models were used. mir-802 was conditionally ablated in acinar cells to study the function of miR-802 in ADM. RESULTS: We show that miR-802 is a highly abundant and acinar-enriched pancreatic miRNA that is silenced during early stages of injury or oncogenic Kras G12Dinduced transformation. Genetic ablation of mir-802 cooperates with Kras G12D by promoting ADM formation. miR-802 deficiency results in de-repression of the miR-802 targets Arhgef12, RhoA, and Sdc4, activation of RhoA, and induction of the downstream RhoA effectors ROCK1, LIMK1, COFILIN1, and EZRIN, thereby increasing F-actin rearrangement. mir-802 ablation also activates SOX9, resulting in augmented levels of ductal and attenuated expression of acinar identity genes. Consistently with these findings, we show that this miR-802-RhoA-F-actin network is activated in biopsies of pancreatic cancer patients and correlates with poor survival. CONCLUSIONS: We show miR-802 suppresses pancreatic cancer initiation by repressing oncogenic Kras-induced ADM. The role of miR-802 in ADM fills the gap in our understanding of oncogenic Kras-induced F-actin reorganization, acinar reprogramming, and PDAC initiation. Modulation of the miR-802-RhoA-F-actin network may be a new strategy to interfere with pancreatic carcinogenesis.

Construction and Investigation of an lncRNA-miRNA-mRNA Regulatory Network of Pancreatic Cancer via bioinformatics analysis

“…Malignant insidious proliferation and metastasis were the primary reasons for unsatis ed prognosis in pancreatic cancer patients. Lots of studies have indicated that miRNAs played essential roles in metastasis and malignant proliferation of pancreatic cancer [22,23]. This study showed miR-130b was obviously decreased in the pancreatic cancer samples.…”

miRSCAPE - inferring miRNA expression from scRNA-seq data

“…Figure 5B shows the two cell populations based on the predicted miRNA profiles. Importantly, miRSCAPE identified several miRNAs that are differentially expressed between the edge and non-edge cells (Figure 5C), that have previously been implicated with proliferation and oncogenesis in pancreatic ductal adenocarcinomas (Ma et al, 2017;Neault et al, 2016;Tang et al, 2013;LaConti et al, 2011;Ge et al, 2022). A few representative examples are illustrated in Figure 5C.…”

Epithelial–mesenchymal transition: The history, regulatory mechanism, and cancer therapeutic opportunities

“…189,190 Aberrant formation of F-actin in cancer cells is closely correlated with EMT and metastasis of a variety of tumors, including hepatocellular carcinoma, glioblastoma, pancreatic cancer, bladder cancer, breast cancer, and so on. 30,[191][192][193][194][195][196][197] Besides, the antagonists for actin polymerization, latrunculin A/B, have been shown anticancer effects through disrupting the formation of F-actin. 30,[198][199][200] This evidence indicates that the organization of actin cytoskeleton network profoundly affects EMT and tumor progression.…”

“…Similarly, Cdc42 interacts with N‐WASP, leading to the activation of Arp2/3 thus playing critical role in actin polymerization 189,190 . Aberrant formation of F‐actin in cancer cells is closely correlated with EMT and metastasis of a variety of tumors, including hepatocellular carcinoma, glioblastoma, pancreatic cancer, bladder cancer, breast cancer, and so on 30,191–197 . Besides, the antagonists for actin polymerization, latrunculin A/B, have been shown anticancer effects through disrupting the formation of F‐actin 30,198–200 .…”