Abstract
BackgroundMicroRNAs can be used in the prognosis of malignancies; however, their regulatory mechanisms are unknown, especially in pancreatic ductal adenocarcinoma (PDAC).MethodsIn 120 PDAC specimens, miRNA levels were assessed by quantitative real time polymerase chain reaction (qRT-PCR). Then, the role of miR-29b-2-5p in cell proliferation was evaluated both in vitro (Trypan blue staining and cell cycle analysis in the two PDAC cell lines SW1990 and Capan-2) and in vivo using a xenograft mouse model. Next, bioinformatics methods, a luciferase reporter assay, Western blot, and immunohistochemistry (IHC) were applied to assess the biological effects of Cbl-b inhibition by miR-29b-2-5p. Moreover, the relationship between Cbl-b and p53 was evaluated by immunoprecipitation (IP), Western blot, and immunofluorescence.ResultsFrom the 120 PDAC patients who underwent surgical resection, ten patients with longest survival and ten with shortest survival were selected. We found that high miR-29b-2-5p expression was associated with good prognosis (p = 0.02). The validation cohort confirmed miR-29b-2-5p as an independent prognostic factor in PDAC (n = 100, 95% CI = 0.305–0.756, p = 0.002). Furthermore, miR-29b-2-5p inhibited cell proliferation, induced cell cycle arrest, and promoted apoptosis both in vivo and in vitro. Interestingly, miR-29b-2-5p directly bound the Cbl-b gene, down-regulating its expression and reducing Cbl-b-mediated degradation of p53. Meanwhile, miR-29b-2-5p expression was negatively correlated with Cbl-b in PDAC tissues (r = − 0.33, p = 0.001).ConclusionsTaken together, these findings indicated that miR-29b-2-5p improves prognosis in PDAC by targeting Cbl-b to promote p53 expression, and would constitute an important prognostic factor in PDAC.
Highlights
MicroRNAs can be used in the prognosis of malignancies; their regulatory mechanisms are unknown, especially in pancreatic ductal adenocarcinoma (PDAC)
Taken together, these findings indicated that miR-29b-2-5p improves prognosis in PDAC by targeting Casitas B-lineage lymphoma (Cbl)-b to promote p53 expression, and would constitute an important prognostic factor in PDAC
We previously studies showed that silencing Cbl-b expression activated the Smad3/p21 axis and inhibited proliferation of PDAC cells [25]
Summary
MicroRNAs can be used in the prognosis of malignancies; their regulatory mechanisms are unknown, especially in pancreatic ductal adenocarcinoma (PDAC). Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumors, with an exceedingly poor prognosis [1]. One of the reasons underlying poor prognosis in pancreatic cancer is that pancreatic cancer cells have a very strong proliferative capacity [3]. MicroRNAs (miRNAs) are non-coding small RNAs, with a length of 20–23 nucleotides [12]. They bind specific target mRNAs in the 3′-untranslated region (UTR), resulting in target mRNA degradation or translation inhibition, which may affect cell proliferation [13].
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