MicroRNA-135a acts as a putative tumor suppressor by directly targeting very low density lipoprotein receptor in human gallbladder cancer.
Bottom Line: Moreover, very low density lipoprotein receptor (VLDLR), which is often upregulated in GBC tissues, was identified as a direct functional target of miR-135a-5p.Furthermore, the p38 MAPK pathway was proven to be involved in miR-135a-VLDLR downstream signaling.Together, these results suggested that the miR-135a-VLDLR-p38 axis may contribute to GBC cell proliferation.
Affiliation: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.Show MeSH
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Mentions: The molecular mechanisms responsible for the effect of miR-135a-5p and VLDLR on GBC cell proliferation remain unclear. The Kyoto Encyclopedia of Genes and Genomes analysis based on mRNA microarray assays showed that the MAPK signal pathway might be involved in the inhibition of miR-135a-5p-induced GBC cell proliferation (Table S2). The protein levels of ERK 1/2, SAPK/JNK, p38, and their phosphorylation levels were detected in the GBC cells infected with GFP lentivirus, miR-135a lentivirus, or both. In both GBC-SD and EH-GB1 cells, VLDLR could reduce the phosphorylation level of p38 (Figs 4c,S4c), and we also found that VLDLR-siRNA could induce phosphorylation of p38 (Fig. S4c). After pretreatment of p38 inhibitor, the miR-135a-induced inhibitory effect on GBC cell proliferation was abrogated (Fig. 5a,b), and the enhanced phosphorylation level of p38 by miR-135a-5p was diminished (Fig. 5c). Furthermore, the miR-135a-5p-induced G1/S arrest could also be abolished by the p38 inhibitor (Fig. 5d), and it was not surprising to find the restoration of suppressed cyclin D1 expression (Fig. 5c), yet the treatment of miR-135a-5p mimic or p38 inhibitor did not significantly affect the protein level of c-MYC in GBC cells (Fig. 5c). Taken together, these results implied that the p38 MAPK pathway is involved in the miR-135a-5p–VLDLR axis on GBC cell proliferation.
Affiliation: Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.