Abstract
BackgroundMicroRNAs (miRNAs) are important regulators that play key roles in tumorigenesis and tumor progression. A previous report has shown that let-7 family members can act as tumor suppressors in many cancers. Through miRNA array, we found that let-7f was downregulated in the highly metastatic potential gastric cancer cell lines GC9811-P and SGC7901-M, when compared with their parental cell lines, GC9811 and SGC7901-NM; however, the mechanism was not clear. In this study, we investigate whether let-7f acts as a tumor suppressor to inhibit invasion and metastasis in gastric cancers.Methodology/PrincipalReal-time PCR showed decreased levels of let-7f expression in metastatic gastric cancer tissues and cell lines that are potentially highly metastatic. Cell invasion and migration were significantly impaired in GC9811-P and SGC7901-M cell lines after transfection with let-7f-mimics. Nude mice with xenograft models of gastric cancer confirmed that let-7f could inhibit gastric cancer metastasis in vivo after transfection by the lentivirus pGCsil-GFP- let-7f. Luciferase reporter assays demonstrated that let-7f directly binds to the 3′UTR of MYH9, which codes for myosin IIA, and real-time PCR and Western blotting further indicated that let-7f downregulated the expression of myosin IIA at the mRNA and protein levels.Conclusions/SignificanceOur study demonstrated that overexpression of let-7f in gastric cancer could inhibit invasion and migration of gastric cancer cells through directly targeting the tumor metastasis-associated gene MYH9. These data suggest that let-7f may be a novel therapeutic candidate for gastric cancer, given its ability to reduce cell invasion and metastasis.
Highlights
Gastric cancer (GC) is the most common gastrointestinal malignancy in East Asia, Eastern Europe, and parts of Central and South America, and is the second leading cause of cancerrelated deaths [1]
We have examined the mRNA expression levels of let-7f in two pairs of human gastric cancer cell lines, GC9811, GC9811-P and SGC7901-NM, SGC7901-M
To further validate the role of let-7f in gastric cancer cells metastasis, we compared the expression levels of let-7f in fresh human gastric cancer tissue specimens with metastases from eight individuals (Table S1), to normal gastric tissues (NG), primary gastric cancer tissues (GC) and distant metastatic gastric cancer tissues (MC), respectively, by real-time PCR
Summary
Gastric cancer (GC) is the most common gastrointestinal malignancy in East Asia, Eastern Europe, and parts of Central and South America, and is the second leading cause of cancerrelated deaths [1]. Metastasis is a complex, multi-step process whereby cancer cells migrate from the primary neoplasm to a distant location [2]. MicroRNAs (miRNAs) are a class of endogenous and small noncoding regulatory RNAs, which regulate genes at the posttranscriptional level [5]. Many reports show that miRNAs play key roles in various biological processes, including cell differentiation, proliferation, apoptosis, stress resistance, fat metabolism, tumorigenesis, and tumor metastasis [7,8,9]. MicroRNAs (miRNAs) are important regulators that play key roles in tumorigenesis and tumor progression. A previous report has shown that let-7 family members can act as tumor suppressors in many cancers. We investigate whether let-7f acts as a tumor suppressor to inhibit invasion and metastasis in gastric cancers
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