Insulin-like growth factor-I induces chemoresistence to docetaxel by inhibiting miR-143 in human prostate cancer

Abstract

Elevated levels of insulin-like growth factor-I (IGF-I) are associated with carcinogenesis and cancer progression. However, the molecular mechanisms by which IGF-I promotes prostate cancer development remain to be elucidated. Docetaxel chemotherapy is an important therapeutic strategy in many types of human cancers including prostate cancer. In this study, we showed that IGF-I rendered PC-3 and DU145 cells more resistant to docetaxel treatment. IGF-I treatment decreased miR-143 expression, but increased the expression levels of IGF-I receptor (IGF-IR) and insulin receptor substrate 1 (IRS1), direct targets of miR-143. Overexpression of miR-143 abolished IGF-I-induced chemoresistance to docetaxel treatment, decreased expression levels of IGF-I, IRS1, and vascular endothelial growth factor (VEGF) in prostate cancer cell lines. Furthermore, docetaxel treatment significantly inhibited VEGF transcriptional activation, whereas IGF-I treatment induced VEGF transcriptional activation in a dose-dependent manner. Forced expression of IGF-IR and IRS1 cDNAs without the 3’ UTR regions restored miR-143-inhibited VEGF transcriptional activation. Finally, miR-143 inhibited tumor growth and made cells more sensitive to docetaxel treatment for decreasing tumor growth in vivo. Taken together, our data demonstrates that IGF-I induces docetaxel resistance and upregulates IGF-IR and IRS1 expression through miR-143 downregulation, whereas miR-143 acts as a tumor suppressor by targeting its targets IGF-IR and IRS1.

Exploring the MIR143-UPAR Axis for the Inhibition of Human Prostate Cancer Cells In Vitro and In Vivo

“…Our results are consistent with data on other cancers, where, upon delivery of MIR143 or MIR145 , an inhibition of pancreatic, breast, or colon carcinoma growth in mice models can be achieved 48, 60, 61. Recently, Niu et al 62 . showed that injection of stably MIR143 -transduced PC-3 cells into mice generated smaller xenograft tumors.…”

Suppression of miR-143 contributes to overexpression of IL-6, HIF-1α and NF-κB p65 in Cr(VI)-induced human exposure and tumor growth

“…RIPA lysis and extraction buffer were used to lyse cells on ice for 30 min as previously described (Niu et al, 2017). Samples were separated by SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to membranes.…”

“…They have been recently implicated in the regulation of tumorigenesis by inhibiting major signaling pathways (Pasquinelli, 2012;Xu et al, 2013;Jiang et al, 2018). Some major signaling pathways have been reported to be influenced by different microRNAs in various diseases, including the PI3K/AKT pathway, MAPK/ERK pathway, the mTOR /p70S6K1 pathway, and the TGFβ signaling pathway (Xu et al, 2012;He et al, 2013;Wang et al, 2014;Niu et al, 2017;Jin et al, 2018;Lam et al, 2018). miR-143 has been demonstrated as a tumor suppressor.…”

Down-Regulation of miR-7 in Gastric Cancer Is Associated With Elevated LDH-A Expression and Chemoresistance to Cisplatin

“…miRNAs have the ability to post-transcriptionally regulate a wide array of genes, with nearly a third of genes thought to undergo some form of miRNA-mediated regulation (Lu et al, 2005). Depending on the specific miRNA and context, these noncoding RNAs can serve to promote or suppress tumor growth, leading to their dysregulation in many cancers (Ling et al, 2013;Niu et al, 2017;Ge et al, 2018). miR-7 has been found in recent years to serve as a tumor suppressor in several tumor types, but its role in GC has not previously been demonstrated.…”