407029

MIR30A

microRNA 30a;MIR30A;microRNA 30a

hsa-mir-30a

6q13

ncRNA

Accumulating data have shown the involvement of microRNAs in cancerous processes as either oncogenes or tumor suppressor genes. Here, we established miR-30a as a tumor suppressor gene in breast cancer development and metastasis. Ectopic expression of miR-30a in breast cancer cell lines resulted in the suppression of cell growth and metastasis in vitro. Consistently, the xenograft mouse model also unveiled the suppressive effects of miR-30a on tumor growth and distal pulmonary metastasis. With dual luciferase reporter assay, we revealed that miR-30a could bind to the 3'-untranslated region of metadherin (MTDH) gene, thus exerting inhibitory effect on MTDH. Furthermore, we demonstrated that silence of MTDH could recapitulate the effects of miR-30a overexpression, while overexpression of MTDH could partially abrogate miR-30a-mediated suppression. Of significance, expression level of miR-30a was found to be significantly lower in primary breast cancer tissues than in the paired normal tissues. Further evaluation verified that miR-30a was negatively correlated with the extent of lymph node and lung metastasis in patients with breast cancer. Taken together, our findings indicated miR-30a inhibits breast cancer proliferation and metastasis by directly targeting MTDH, and miR-30a can serve as a prognostic marker for breast cancer. Manipulation of miR-30a may provide a promising therapeutic strategy for breast cancer treatment.

BACKGROUND: MicroRNAs (miRNAs) are regulators of gene expression in tumor development and progression. However, their influence on metastasis of clear cell renal cell carcinoma (ccRCC) is less understood. To determine the role of miRNAs in metastatic progression, miRNA expression in primary ccRCC was compared to distant metastases. METHODS: Total RNA of 53 primary ccRCCs, 35 distant metastases from lung, bone, brain, and abdomen, as well as 17 normal kidney tissues was isolated from fresh frozen tissue and formalin-fixed paraffin-embedded (FFPE) samples. The miRNA microarrays were performed based on fresh frozen tissue. Results were validated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) on fresh frozen tissue and FFPE samples. Real-time cell analyses and transwell invasion assays were carried out after transient transfection of microRNA-30c (miR-30c) in cell line 786-O. RESULTS: There were 14 miRNAs differently expressed in metastatic primary ccRCC and distant metastases compared to non-metastatic primary tumors. A strong correlation of miRNAs to progression-free- and cancer-specific 5-year-survival was determined. Specific miRNAs were differently expressed in distant metastases compared to primary ccRCC. A miRNA signature distinguished lung metastases from other metastatic sites. Overexpression of miR-30c increased adherence and decreased migration and invasion in the ccRCC cell line. CONCLUSIONS: MiRNAs are deregulated in metastatic primary ccRCC and could be promising prognostic markers for an early prediction of metastasis. Alterations in miRNA expression characterize distant metastases of different metastatic sites. Furthermore, our study suggests a functional role of miR-30c in metastasis. The miRNAs could be a helpful tool for individual follow-up prediction and personalized therapy selection.

BACKGROUND/AIMS: MicroRNAs (miRNAs) play key roles in tumor metastasis. The aim of this study was to determine the regulation and function of miR-30a in colorectal carcinoma (CRC) metastasis. METHODS: The expression of miR-30a was detected in CRC cell lines and samples by qRT-PCR. The anti-metastatic effect of miR-30a was determined by both in vitro and in vivo assays. A luciferase reporter assay was performed to determine target association between miR-30a and phosphoinositide 3-kinase catalytic subunit delta (PIK3CD). RESULTS: miR-30a was significantly downregulated in highly metastatic CRC cell lines and metastatic tissues. Overexpression of miR-30a suppressed CRC cell migration and invasion in vitro and liver metastasis in vivo, whereas miR-30a deletion dramatically promoted cell migration and invasion. Further studies revealed that PIK3CD is a direct target of miR-30a as miR-30a bounds directly to the 3'-UTR of PIK3CD, subsequently reducing its expression. Similar to the restoring miR-30a expression, PIK3CD downregulation inhibited cell migration and invasion, whereas PIK3CD overexpression rescued the suppressive effect of miR-30a. Moreover, significant downregulation of miR-30a in metastatic CRC tissues was found to be inversely correlated with PIK3CD expression. Mechanistic studies revealed that miR-30a down-regulated the expression of key components of the Akt/mTOR pathway, whereas PIK3CD overexpression reversed this negative effect. CONCLUSION: Our findings indicate that miR-30a might function as a metastasis suppressor in CRC. miR-30a may be a potential therapeutic target to block CRC metastasis.

The pathological relevance and significance of microRNAs (miRNAs) in hepatocarcinogenesis have attracted much attention in recent years; however, little is known about the underlying molecular mechanisms through which miRNAs are involved in the development and progression of hepatocellular carcinoma (HCC). In this study, we demonstrate that miR-30d is frequently up-regulated in HCC and that its expression is highly associated with the intrahepatic metastasis of HCC. Furthermore, the enhanced expression of miR-30d could promote HCC cell migration and invasion in vitro and intrahepatic and distal pulmonary metastasis in vivo, while silencing its expression resulted in a reduced migration and invasion. Galphai2 (GNAI2) was identified as the direct and functional target of miR-30d with integrated bioinformatics analysis and messenger RNA array assay. This regulation was further confirmed by luciferase reporter assays. In addition, our results, for the first time, showed that GNAI2 was frequently suppressed in HCC by way of quantitative reverse-transcription polymerase chain reaction and immunohistochemical staining assays. The increase of the GNAI2 expression significantly inhibits, whereas knockdown of the GNAI2 expression remarkably enhances HCC cell migration and invasion, indicating that GNAI2 functions as a metastasis suppressor in HCC. The restoration of GNAI2 can inhibit miR-30d-induced HCC cell invasion and metastasis. CONCLUSION: The newly identified miR-30d/GNAI2 axis elucidates the molecular mechanism of HCC cell invasion and metastasis and represents a new potential therapeutic target for HCC treatment.

BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs that regulate physiological and pathological processes by suppressing target gene expression. Altered expression of miR-30a-3p has been demonstrated in several cancers. However, little about how miR-30a-3p functions in these cancers has been reported, and the role of miR-30a-3p in hepatocellular carcinoma (HCC) is unknown. The purpose of this study was to identify the role and underlying molecular mechanism of action of miR-30a-3p in HCC. METHODS: A total of 110 HCC patients, primarily treated by surgical removal of tumors, were involved in the study. HCC cell line Bel-7402 was selected to characterize the function of miR-30a-3p in vitro. RESULTS: Our results showed that in 83.6% of the 110 HCC patients, expression of miR-30a-3p was significantly downregulated (P < 0.0001) in tumors compared to adjacent normal tissues. In a clinicopathological correlation analysis, downregulation of miR-30a-3p correlated with a significantly higher incidence of portal vein tumor thrombus (PVTT, P = 0.009). Moreover, miR-30a-3p markedly inhibited the invasion and migration of Bel-7402 HCC cells in vitro. Furthermore, miR-30a-3p overexpression had an inhibitory effect on cell proliferation, induced apoptosis and increased arrest of cells in the S phase. We further demonstrated that miR-30a-3p regulates HCC cell function by a mechanism involving reduced vimentin and MMP3 expression and restoration of E-cadherin expression. CONCLUSIONS: our data suggest that miR-30a-3p is downregulated in HCC and acts as a tumor suppressor in vitro. Regulation of vimentin, E-cadherin and MMP3 by miR-30a-3p suggests a useful therapeutic strategy for tumors with reduced miR-30a-3p expression.

MicroRNAs (miRNAs) are small non-coding RNAs which regulate gene expression by base-pairing to the 3'-UTR of the target mRNA. Recently, miRNAs have been shown to regulate cancer metastasis, however, central molecular mechanisms of this ability still need to be investigated. Epithelial to mesenchymal transition (EMT), which is characterized especially by repression of E-cadherin expression and increased cell motility, is an essential component of cancer metastasis and progression. In the present study, we found that Snai1, a known transcriptional repressor of E-cadherin and modulator of EMT, is post-transcriptionally targeted by miRNA-30a in non-small cell lung cancer (NSCLC). Consistent with this, microRNA-30a expression was found inversely proportional to the invasive potential of various NSCLC cell lines, correlating positively with E-cadherin (epithelial marker) and negatively with N-cadherin (mesenchymal marker) expression. Forced re-introduction of miR-30a significantly altered cell morphology, in vitro invasion and migration of invasive cell lines, this being paralleled by a downregulation of Snai1 and upregulation of E-cadherin expression. Using a chicken embryonic metastasis assay, we found that miR-30a suppresses in vivo distant metastasis to the lungs and liver. Finally, we screened the expression of miR-30a in 64 consecutively resected NSCLC patients and found that, in 81% of the patients, expression of miR-30a was downregulated significantly (p < 0.0001) in tumors compared to corresponding normal tissues. These results suggest that miR-30a targets Snai1, inhibits invasion and metastasis, and is downregulated in NSCLC.