Suppression of tumor cell invasiveness and in vivo tumor growth by microRNA-874 in non-small cell lung cancer

Abstract

MicroRNAs are a novel family of small non-coding RNAs that regulate the expression of several genes involved in normal development as well as human disorders including cancer. Here we show that miR-874 plays a tumor suppressor role in non-small cell lung cancer (NSCLC) in vitro and in vivo. In silico target prediction analysis revealed numerous genes associated with tumor progression including MMP-2 and uPA as the putative target genes of miR-874. Our preliminary in situ hybridization experiments demonstrated the diminution of miR-874 expression in lung cancer tissues compared to their normal counter parts. Overexpression of miR-874 in CD133-positive cancer stem cell (CSC) population led to a significant loss in CSC-phenotype and enhanced sphere de-differentiation into epithelial-like cells. Restoration of miR-874 expression drastically reduced cell invading ability in comparison to mock and control-miR-treated cells by suppressing the protein levels of MMP-2 and uPA. In in vivo experiments, miR-874 treatment decreased orthotopic tumor growth in nude mice compared to mock and control-miR treatments. Further, the immunoreactivity of human anti-MMP-2 and anti-uPA was significantly reduced in tumor sections from mice that received miR-874 treatment. In conclusion, our study highlights the possible tumor suppressor role of miR-874 in NSCLC-initiating cells and suggests miR-874 as a potential target in the treatment of NSCLC.

Decreased expression of miR-874 and its tumor suppressive function in human colorectal cancer

“…In vitro, ectopic miR-874 expression suppressed tumor cell proliferation and promoted cell apoptosis in head and neck squamous cell carcinoma (Nohata et al, 2013), breast cancer , and gastric cancer (Jiang et al, 2014). Upregulation of miR-874 also reduced the cell-invading ability of non-small cell lung cancer and maxillary sinus squamous cell carcinoma cells (Nohata et al, 2011;Kesanakurti et al, 2013). In vivo, Jiang et al (2014) found that there was decreased miR-874 expression, which correlated with poor tumor differentiation, lymph node metastasis, and advanced tumor stage in patients with gastric cancer.…”

“…miR-874 has been observed to be downregulated in maxillary sinus squamous cell carcinoma (Nohata et al, 2011), gastric cancer Jiang et al, 2014;Zhang et al, 2015), non-small cell lung cancer (Kesanakurti et al, 2013), and breast cancer , and acts as a candidate tumor suppressor in these tumors. However, the potential role of miR-874 in the regulation of CRC tumorigenesis is still unknown.…”

“…miR-874 is located on chromosome 5q31.2, which is a well-known frequent fragile site in the human genome that is often deleted in cancers and genetic disorders, and this site is also specifically correlated with chromosomal rearrangements in cancer (Kesanakurti et al, 2013). miR-874 has been observed to be downregulated in maxillary sinus squamous cell carcinoma (Nohata et al, 2011), gastric cancer Jiang et al, 2014;Zhang et al, 2015), non-small cell lung cancer (Kesanakurti et al, 2013), and breast cancer , and acts as a candidate tumor suppressor in these tumors.…”

Serum Levels of miR-19b and miR-146a as Prognostic Biomarkers for Non-Small Cell Lung Cancer

“…By contrast, some downregulated miRNAs may act as cancer inhibitors by negatively modulating oncogenes or genes that inhibit cell differentiation and apoptosis (Iorio and Croce 2009). Many studies have shown that miRNAs participate in tumorigenesis and progression of various types of cancer, including lung (Chen et al 2013a;Kesanakurti et al 2013), breast (Li et al 2012a;Wang et al 2013a), gastric (Zhou et al 2013) and colorectal cancers (Dassow and Aigner 2013). Since miRNAs have important roles in tumorigenesis and cancer progression, miRNAs may also be a potential target for cancer treatment (van Kouwenhove et al 2011;Dassow and Aigner 2013;Shen et al 2013).…”

MiRNA Molecular Profiles in Human Medical Conditions: Connecting Lung Cancer and Lung Development Phenomena

“…Other examples of miRNAs associated with lung cancer suppression are miRNA-126, miR-874, miR-133b, miR-100 and miR-145 which are downregulated in lung tumor cells. Upregulation of VEGF in one study was inverse to MiR-126 expression, and miR-145 in NSCLC tumor cells showed to act as a tumor suppressor and pro-apoptotic molecule (Bhaskaran et al, 2009;Liu et al, 2012a;Liu et al, 2012b;Kesanakurti et al, 2013). Down-regulation of miR-125a-3p and miR-125a-5p in NSCLCs predicted to be an aggressive clinical course by promoting tumor invasion and lymph node metastasis.…”