Mitigation of arsenic-induced acquired cancer phenotype in prostate cancer stem cells by miR-143 restoration

Abstract

Inorganic arsenic, an environmental contaminant and a human carcinogen is associated with prostate cancer. Emerging evidence suggests cancer stem cells (CSCs) are the driving force of carcinogenesis. Chronic arsenic exposure malignantly transforms the human normal prostate stem/progenitor cell (SC) line, WPE-stem to arsenic-cancer SCs (As-CSCs), through unknown mechanisms. MicroRNAs (miRNAs) are small, non-coding RNAs that negatively regulate gene expression at the posttranscriptional level. In prior work, miR-143 was markedly downregulated in As-CSCs, suggesting a role in arsenic-induced malignant transformation. In the present study, we investigated whether loss of miR-143 expression is important in arsenic-induced transformation of prostate SCs. Restoration of miR-143 in As-CSCs was achieved by lentivirus-mediated miR-143 overexpression. Cells were assessed bi-weekly for up to 30 weeks to examine mitigation of cancer phenotype. Secreted matrix metalloproteinase (MMP) activity was increased by arsenic-induced malignant transformation, but miR-143 restoration decreased secreted MMP-2 and MMP-9 enzyme activities compared with scramble controls. Increased cell proliferation and apoptotic resistance, two hallmarks of cancer, were decreased upon miR-143 restoration. Increased apoptosis was associated with decreased BCL2 and BCL-XL expression. miR-143 restoration dysregulated the expression of SC/CSC self-renewal genes including NOTCH-1, BMI-1, OCT4 and ABCG2. The anticancer effects of miR-143 overexpression appeared to be mediated by targeting and inhibiting LIMK1 protein, and the phosphorylation of cofilin, a LIMK1 substrate. These findings clearly show that miR-143 restoration mitigated multiple cancer characteristics in the As-CSCs, suggesting a potential role in arsenic-induced transformation of prostate SCs. Thus, miR-143 is a potential biomarker and therapeutic target for arsenic-induced prostate cancer.

miR-143 Regulates Memory T Cell Differentiation by Reprogramming T Cell Metabolism

“…The downregulation of miR-143 has been reported in ESCC, gastric cancer, colon cancer, prostate cancer, breast cancer, lung cancer, and several other cancers (20)(21)(22)(23)(24). Besides the critical roles in tumorigenesis, miRNAs have emerged as crucial regulators of T cell differentiation and function.…”

miR-143-3p inhibits the proliferation, migration and invasion in osteosarcoma by targeting FOSL2

“…The down-regulation of miR-143 expression has also been reported in several human cancers, including colorectal cancer 23 , prostate cancer 26 , cervical cancer 27 , ovarian cancer 28 and B-cell lymphoma 29 . Thus, it is considered that miR-143 is a tumor-suppressor miRNA.…”

The role of microRNAs in metal carcinogen-induced cell malignant transformation and tumorigenesis

“…One recent study has shown that miR-143 was significantly down-regulated in Cr(VI)-transformed human bronchial epithelial BEAS-2B cells (He et al, 2013). As discussed above, the expression level of miR-143 was also found to be significantly decreased in arsenic-transformed human prostate stem cells and miR-143 re-expression greatly reduced malignant phenotypes of arsenic-transformed cells (Ngalame et al, 2014, 2015). Similarly, re-expression of miR-143 in Cr(VI)-transformed BEAS-2B cells significantly reduced their malignant phenotypes as evidenced by decreased mouse xenograft tumor angiogenesis and tumor growth (He et al, 2013).…”

“…The authors concluded that arsenic induces malignant cellular transformation of human prostate cells by dysregulating the cellular miRNA profiles, which leads to an increase in the activation of oncogenic pathways such as RAS. Indeed, a recent follow-up study from the same group showed that restoration of miR-143, one of the significantly down-regulated miRNAs in arsenic-transformed prostate stem cells (As-CSC), greatly reduced multiple malignant phenotypes in the As-CSCs (Ngalame et al, 2015). …”