Mir-135a enhances cellular proliferation through post-transcriptionally regulating PHLPP2 and FOXO1 in human bladder cancer

Abstract

BackgroundBladder cancer is the most common malignancy in urinary system and the ninth most common malignancy in the world. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression by targeted repression of transcription and translation and play essential roles during cancer development. We investigated the expression of miR-135a in bladder cancer and explored its bio-function during bladder cancer progression.MethodsThe expression of miR-135a in bladder cancer cells and tissues are performed by using Real-time PCR assay. Cell viability assay (MTT assay), colony formation assay, anchorage-independent growth ability assay and Bromodeoxyuridine labeling and immunofluorescence (BrdUrd) assay are used to examine cell proliferative capacity and tumorigenicity. Flow cytometry analysis is used to determine cell cycle progression. The expressions of p21, p27, CyclinD1, Ki67, PHLPP2 and FOXO1 are measured by Western blotting assay. Luciferase assay is used to confirm whether FOXO1 is the direct target of miR-135a.ResultsmiR-135a is upregulated in bladder cancer cells and tissues. Enforced expression of miR-135a promotes bladder cancer cells proliferation, whereas inhibition of miR-135a reverses the function. Furthermore, for the first time we demonstrated PHLPP2 and FOXO1 are direct targets of miR-135a and transcriptionally down-regulated by miR-135a. Suppression of PHLPP2 or FOXO1 by miR-135a, consisted with dysregulation of p21, p27, Cyclin D1 and Ki67, play important roles in bladder cancer progression.ConclusionOur study demonstrates that miR-135a promotes cell proliferation in bladder cancer by targeting PHLPP2 and FOXO1, and is performed as an onco-miR.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0438-8) contains supplementary material, which is available to authorized users.

CircRNA-Cdr1as Exerts Anti-Oncogenic Functions in Bladder Cancer by Sponging MicroRNA-135a

“…6H). A previous study reported that miR-135a promotes the proliferation and cell cycle progression of bladder cancer and inhibits the expression of p21 in bladder cancer [26]. The result was validated in the miR-135a-transfected EJ and T24 cells (Fig.…”

“…It also purportedly promotes tumour formation in bladder cancer and suppresses p21 expression [26]. We detected the expression level of p21 in miR-135a- or Cdr1as-transfected cells.…”

Hydroxytyrosol supplementation modulates the expression of miRNAs in rodents and in humans

“…miR-483-3p has been also associated with the capacity of adipocytes to store lipids and dysregulation of its expression could directly inhibit adipose tissue expandability and lipid storage, which in turn affect other tissues by stimulating ectopic triglyceride storage and lipotoxicity [36]. Regarding the other miRNAs and their function, miR-196b has been associated with inflammatory bowel disease [37], insulin [38] and cancer [39]; miR-346 has been implicated in rheumatoid arthritis [40], osteogenic differentiation [41] and cancer [42]; miR-1247 was implicated in cancer [43,44]; miR135a was implicated in proliferation [45], inflammation [46] and calcification [47]; and miR-193a-5p was associated with cancer [48,49]. Although their effects in the intestine need to be evaluated, it is clear that HT could specifically modulate their expression and exert biological effects through this mechanism.…”

miR-135a Protects Dextran Sodium Sulfate-Induced Inflammation in Human Colorectal Cell Lines by Activating STAT3 Signal

“…A number of miRNAs are highly associated with the initiation, development, and progression of IBD, but some also exert anti-inflammatory effect and may have the potential to be used as therapeutic targets [21,22], such as miR-135a. Previous studies indicated that miR-135a abundance was dramatically reduced in diseases and tumor tissues [23,24], suggesting a novel therapeutic potential in diseases, especially for cancers. For example, miR-135a has been evaluated to predict lymph node metastasis and tumor stage in gastric cancer [25] and acts as a tumor suppressor in gastric cancer through targeting Kinesin family member C1 [26].…”