microRNA-451 Regulates Macrophage Migration Inhibitory Factor Production and Proliferation of Gastrointestinal Cancer Cells

Abstract

Purpose: microRNAs (miRNA) are small RNAs that function as post-transcriptional regulators of gene expression. Recent evidence has shown that some miRNAs can act as oncogenes or tumor suppressors. This study was conducted to evaluate the potential association of miRNA expression with clinical outcome in patients with gastric cancer. Experimental Design: Expression of 250 human mature miRNAs was measured by real-time PCR on paraffin-embedded tumor samples of 21 patients with gastric cancer stage III uniformly treated with surgical resection followed by chemoradiation. We identified the miRNAs correlated with disease-free and overall survival times, and the results were evaluated including 24 other patients. In vitro cell proliferation and radiosensitivity studies were done to support clinical data. Results:The results revealed that down-regulation of miR-451was associated with worse prognosis. miR-451 was detected by in situ hybridization in epithelial cells and showed decreased expression in gastric and colorectal cancer versus nontumoral tissues. Overexpression of miR-451in gastric and colorectal cancer cells reduced cell proliferation and increased sensitivity to radiotherapy. Microarray and bioinformatic analysis identified the novel oncogene macrophage migration inhibitory factor (MIF) as a potential target of miR-451. In fact, overexpression of miR451down-regulated mRNA and protein levels of MIF and decreased expression of reporter genes with MIF target sequences. Moreover, we found a significant inverse correlation between miR451and MIF expression in tumoral gastric biopsies. Conclusions: These findings support the role of miR-451as a regulator of cancer proliferation and opennew perspectives for the development of effective therapies for chemoradioresistant cancers.

The Potential Role of miR-451 in Cancer Diagnosis, Prognosis, and Therapy

“…Of note, the expression of miR-451 is downregulated in patients who did not respond to irinotecan-based first-line therapy compared with responding patients. A same study showed that miR-451 combined with imatinib mesylate had a cooperative effect on growth inhibition of glioblastoma stem cells (16). Similarly, higher expression of miR-451 and miR-15b in pretreatment osteosarcoma samples correlated with subsequent positive response to neoadjuvant chemotherapy (58).…”

“…miR-29b, miR-29c, miR-19b, miR-31, miR-148a, and miR-451 were highly expressed in gastric tissue and could be considered as a part of the miRNA expression pattern of healthy gastric tissue (47). Likewise, another study detected miR-451 expression in epithelial cells by in situ hybridization and found that miR-451 expression was decreased in gastric and colorectal cancer tissues compared with nontumor tissues (16). We previously also observed that miR-451 was significantly downregulated by 170.9-fold comparing non-small cell lung carcinoma (NSCLC) tissues with corresponding noncancerous tissues (14,15).…”

“…Early studies have also highlighted the roles of miR-144/451 in human cancers. Many studies have established that miR-451 is widely dysregulated in human malignancies, including in lung cancer (14,15), gastric cancer (16), breast cancer (17,18), glioma (19)(20)(21), and leukemia (22), indicating that miR-451 might play a critical role in oncogenesis. In this review, we focus on the noncanonical biogenesis pathway for miR-451 and its roles in erythroid differentiation.…”

The microRNA network and tumor metastasis

“…Tsuchiya et al (2009) showed that miR-338-3p and miR-451 contributed to the formation of epithelial basolateral polarity by facilitating translocalization of b1-integrin to the basolateral membrane in an epithelial differentiation model. Moreover, miR-451 can also regulate cancer proliferation and metastasis through targeting macrophage migration inhibitory factor (Bandres et al, 2009). Another tumor suppressor miRNA, miR-122, negatively impacts hepatocellular carcinoma intrahepatic metastasis by suppressing angiogenesis, and exerts its action through regulation of the disintegrin and metalloprotease 17 (ADAM17) .…”

MicroRNA-451 Inhibits Growth of Human Colorectal Carcinoma Cells via Downregulation of Pi3k/Akt Pathway

“…The upregulation level of miR-31 was related to the pathological stage of CRC. CRC expression was significantly higher at stage IV than at stage II, indicating that miR-3l could induce tumors and render them with more invasive phenotype, and that miR-31 showed certain clinical effect in staging of CRC (Bandres et al, 2009) used qRT-PCR to examine the expressions of 250 types of miRNAs in the tissues of 21 gastric cancer patients, and the clinical pathological analysis showed that miR-451 was associated with the poor prognosis of gastric cancer patients. In-situ hybridization showed that the expressions of miR-451 decreased in epithelia of gastric cancer and colon cancer patients.…”