Simultaneous overexpression of miR-126 and miR-34a induces a superior antitumor efficacy in pancreatic adenocarcinoma

Abstract

BackgroundPancreatic adenocarcinoma (PAC) is one of the most fatal cancers due to its high degree of malignancy, increasing incidence, high mortality, and unsatisfactory treatment efficacy. Evidence has suggested that numerous microRNAs (miRNAs), including miR-126 and miR-34a, have potent tumor-suppressing effects on PAC, implicating a possible application of miRNA in tumor therapy. However, the therapeutic effect of a single miRNA on pancreatic cancer is limited.MethodsWe simultaneously delivered miR-126 and miR-34a into PAC cells by a carcinoembryonic antigen promoter-driven oncolytic adenovirus (AdCEAp-miR126/34a), and examined the antitumor efficacy of the therapeutic system in in vitro and in vivo experiments.ResultsIn vitro cytological experiments found that the expression levels of miR-126 and miR-34a were specifically increased in the AdCEAp-miR126/34a-infected PAC cells, and the antitumor efficacy was enhanced in aspects of cancer cell viability, migration, invasion, and apoptosis, by synergistically combining the antitumor effects of overexpressed miR-126 and miR-34a and the oncolytic effect of viral replication specifically in PAC cells. The expression levels of miR-126 target genes (vascular endothelial growth factor-A and SOX2) and miR-34a target genes (cyclin D1, E2F1, and Bcl-2) were markedly decreased in the PAC cells after being infected with AdCEAp-miR126/34a. Notable suppression of the therapeutic system on tumor growth was also proven in established PAC xenograft tumor models in nude mice, which demonstrated that the combination of miR-126 and miR-34a exerts more effective antitumor outcomes than a single miRNA.ConclusionThe therapeutic system co-expressing miR-126 and miR-34a mediated by oncolytic adenovirus is a promising system for PAC target therapy.

Simultaneous downregulation of miR-21 and upregulation of miR-7 has anti-tumor efficacy

“…In order to improve outcomes, simultaneously targeting both miR-21 and miR-7 pathways offers a promising strategy as they target parallel cell survival pathways and produce a synergistic effects 48,49 . Although there are few reports on forced co-expression or co-inhibition of miRNAs in cancer study [50][51][52][53] , none of the previous studies have shown simultaneous inhibition and overexpression of different miRs in the same tumor. In one study, Dong et al showed www.nature.com/scientificreports www.nature.com/scientificreports/ co-inhibition of miR-21 and miR-10b can significantly induce apoptosis and reduce cell invasion in human GBM 50 .…”

circZMYM2 Competed Endogenously with miR-335-5p to Regulate JMJD2C in Pancreatic Cancer

“…Pancreatic cancer (PC) ranks among the top deadly cancers in that it generates threatening malignancies and is affecting an increasing number of victims [1]. Being fatal yet asymptomatic, PC is a prevalent cause of cancer-associated mortality [2].…”

“…It is often featured by resistance to chemotherapy treatment, which blocked satisfactory treatment of this malignancy [3]. It has been reported that quite a few microRNAs (miRNAs) are potently PCinhibitory, implicating the possibility of therapeutic miRNA-application [1]. Thus, this study intends to unearth the underlying molecular mechanism in pancreatic cancer.…”

“…Emerging studies have described anomal expressions of miRNAs in PC, which tend to interact with the proliferation, apoptosis and cell cycle phases of PC cells by manipulating different molecules or signaling pathways [8]. For instance, the co-expression of miR-126 and miR-34a as introduced by oncolytic adenovirus is prospecting in PC target therapy [1]. However, the potential involvement of miR-355 has not been studied in pancreatic cancer.…”

<p>A Systemic Review on the Regulatory Roles of miR-34a in Gastrointestinal Cancer</p>

“…166 Moreover, Feng et al found that simultaneous overexpression of miR-34a and miR-126 had strong anti-tumor effects in PC. 167 In addition to using miRNAs to enhance anti-tumor effects, another study reported that the combination of miR-34a and polo like kinase 1 (PLK1) siRNA delivered by biodegradable amphiphilic polyglutamate amine polymer nanocarrier (APA) markedly enhanced anti-tumor effects of miR-34a in the treatment of PC. 168 These studies demonstrated potential clinical applications of miR-34a in the treatment of PC.…”