The role of miR-203 and miR-34a in EGFR activation prostate cancer metastasis

It has been shown that miR-203 plays a critical role in prostate cancer and decreased miR-203 expression was also shown in clinical metastatic prostate cancer. However, the biological function of miR-203 that suppresses metastasis of SRC-activated prostate cancer cells remains unclear. Our preliminary data showed that patients with low canonical AR gene signatures displayed correlated high SRC levels and activated AR induced miR-203 expression reduced SRC levels in prostate cancer model systems. miR-203 directly binds to the 3’ UTR of SRC and regulates the stability of SRC mRNA in the manner of AR activation. Moreover, we found that progressive prostate cancer cell migration and growth were associated with decreased AR-regulated miR-203 and increased SRC. Relationships among the AR, miR-203, and SRC were also confirmed in clinical dataset and specimens. We anticipate that the induction of SRC results in increased prostate cancer metastasis that is linked to dysregulation of the AR signaling pathway through inactivation of miR-203. Loss of heterozygosity of the ETV6 (ETS variant gene 6/TEL) allele is observed in many solid tumors and indicates that ETV6 might have characteristics of a tumor suppressor. It has not been established that ETV6 actually acts as a tumor suppressor in prostate cancer and whether EGFR-dependent influences on ETV6 activity are mechanistically linked. Our preliminarily results identified that miR-96, a potential oncomiR, as a novel target of nuclear EGFR in prostate cancer cells. We further identified ETV6 as a downstream target of miR-96 and found that EGFR-mediated activation of miR-96 leads to decreased expression of ETV6. It is well established that enhanced EGFR is correlated with disease relapse and progression to androgen-independence in many lethal prostate cancers. However, it is unclear what targetable signaling components are involved in the nuclear EGFR signaling network, and which nuclear EGFR targets are most important for progression phenotypes. Our preliminarily results found that activation of EGFR stimulates TWIST1 through reduced ETV6-mediated specifically targeting to the promoter of TWIST1 that affect bone metastatic capability of prostate cancer. We observed that in clinical samples gene expression signatures associated with EGFR signaling are associated with prostate cancer progression, low ETV6 expression, and high TWIST1 expression. These results present a novel mechanism contributing to the bone metastatic phenotype observed in a subset of lethal, advanced prostate cancers, in which ETV6 levels are downregulated, resulting in the overexpression of EGFR-TWIST1 signaling. The regulatory mechanism, especially as related to EGFR signaling pathway and ETV6 regulation, is an unsolved question and is my studies.