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MiR19b-3p promotes the growth and metastasis of colorectal cancer via directly targeting ITGB8.

ABSTRACT: MicroRNAs (miRNAs) are widely up-regulated or down-regulated in a variety of tumors, including lung cancer, liver cancer, and colorectal cancer (CRC). Furthermore, miRNAs can function as tumor suppressors or proto-oncogenes by controlling the growth and metastasis of cancer cells. In the present study, we found a significant increase in miR19b-3p levels in CRC compared to tumor tissue and revealed the role of miR19b-3p in CRC growth and metastasis. The exogenous overexpression of miR19b-3p induced the proliferation, migration, and invasion of CRC cells in vitro. In addition, the nude mouse xenograft model showed that miR19b-3p overexpression promoted CRC growth and lung metastasis in vivo, whereas silencing miR19b-3p showed opposite results. Mechanistic studies have shown that the integrin beta-8 (ITGB8) transcript is one of the direct targets of miR19b-3p, and the expression of ITGB8 in CRC specimens was positively correlated with miR19b-3p. Finally, ectopic expression of ITGB8 rescued cell proliferation and invasion, which was inhibited by down-regulation of miR19b-3p. In addition, knockdown of ITGB8 neutralized the effects of miR19b-3p overexpression on cell growth and metastasis in CRC cells. Together, these results suggest that the miR19b-3p/ITGB8 axis plays an important role in the growth and metastasis of CRC.

SUBMITTER: Huang L

PROVIDER: S-EPMC5665847 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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miR19b-3p promotes the growth and metastasis of colorectal cancer via directly targeting ITGB8.

Huang Liang L Cai Jin Lin JL Huang Pin Zhu PZ Kang Liang L Huang Mei Jin MJ Wang Lei L Wang Jian Ping JP

American journal of cancer research 20171001 10

MicroRNAs (miRNAs) are widely up-regulated or down-regulated in a variety of tumors, including lung cancer, liver cancer, and colorectal cancer (CRC). Furthermore, miRNAs can function as tumor suppressors or proto-oncogenes by controlling the growth and metastasis of cancer cells. In the present study, we found a significant increase in miR19b-3p levels in CRC compared to tumor tissue and revealed the role of miR19b-3p in CRC growth and metastasis. The exogenous overexpression of miR19b-3p induc ...[more]

PMID: 29119049

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Project description:BackgroundColorectal cancer is one of the most common malignancy in the world. It has been reported that cancer stem cells (CSCs) serve as the primary drivers of tumorigenesis and tumor progression. There is an urgent need to explore novel molecules that regulate CSCs or their signatures. Increasing evidence has shown that miRNAs are involved in tumorigenesis and progression. Here, we aim to explore the regulatory effect and mechanism of miR-3065-3p on the stemness of colorectal cancer.MethodsThe expression of miR-3065-3p in colorectal cancer and the association of miR-3065-3p expression with prognosis of patients with colorectal cancer were analyzed using TCGA dataset or clinical cases. Gain or loss of function in different models, including colorectal cancer cell lines and orthotopic xenograft or liver metastatic mouse model, were used to investigate the effects of miR-3065-3p on colorectal cancer stemness and metastasis in vitro and in vivo. Cancer stemness was analyzed by detecting the ability of migration and invasion, NANOG, OCT4, and SOX2 expression, ALDH activity and sphere formation. In addition, the interaction of miR-3065-3p and cytokine receptor-like factor 1 (CRLF1) was analyzed theoretically and identified by the luciferase reporter assay. Moreover, the correlation between CRLF1 expression and miR-3065-3p was analyzed in colorectal cancer tissues. Finally, the effect of CRLF1 on the stemness and metastasis of colorectal cancer in vitro and in vivo was assessed.ResultsIn this report, we found that miR-3065-3p was overexpressed in colorectal cancer and that its high expression was associated with poor prognosis of patients with colorectal cancer. miR-3065-3p promotes the stemness and metastasis of colorectal cancer. Furthermore, CRLF1 was the downstream target of miR-3065-3p and inhibited the stemness of colorectal cancer. In addition, CRLF1 expression was negatively correlated with miR-3065-3p in colorectal cancer tissues. And, CRLF1 mediated the effects of miR-3065-3p on promoting stemness of colorectal cancer cells.ConclusionOur data suggest that miR-3065-3p promoted the stemness and metastasis of colorectal cancer by targeting CRLF1. miR-3065-3p might serve as a promising prognostic marker as well as a therapeutic target for colorectal cancer.

Project description:Background: MiR-146b has been reported to be overexpressed in papillary thyroid cancer (PTC) tissues and associated with aggressive PTC. MiR-146b is regarded as a relevant diagnostic marker for this type of cancer. MiR-146b-5p has been confirmed to increase cell proliferation by repressing SMAD4. However, detailed functional analysis of another mature form of miR-146b, miR-146b-3p, has not been carried out. This study aimed to identify the differential expression of miR-146b-5p and miR-146b-3p in more aggressive PTC associated with lymph node metastasis, and further elucidate the contribution and mechanism of miR-146b-3p in the process of PTC metastasis. Methods: Expression of miR-146b-5p and miR-146b-3p was assessed in formalin-fixed paraffin-embedded tissue samples from PTC patients, and the relationship with lymph node metastasis was analyzed. A variety of PTC cells, including BHP10-3, BHP10-3SCmice, and K1 cells, were cultured and treated with miR-146b-5p or miR-146b-3p mimics/inhibitors. The cell migration and invasion abilities were characterized by the real-time cell analyzer assay and Transwell™ assay. PTC xenograft models were used to examine the effect of miR-146b-3p on PTC metastatic ability in vivo. Direct downstream targets of miR-146b-3p were analyzed by luciferase reporter assay and Western blotting. The mechanism by which miR-146b-3p affects cell metastasis was further characterized by co-transfection with merlin, the protein product of the NF2 gene. Results: MiR-146b-5p and miR-146b-3p expression was significantly higher in thyroid cancer tissues and cell lines than in normal thyroid tissue and cells. Moreover, expression of miR-146b-5p and miR-146b-3p was further increased in thyroid metastatic nodes than in thyroid cancer. After overexpression of miR-146b-5p or miR-146b-3p in BHP10-3 or K1 cells, PTC migration and invasion were increased. Notably, miR-146b-3p increased cell migration and invasion more obviously than did miR-146b-5p. Overexpression of miR-146b-3p also significantly promoted PTC tumor metastasis in vivo. Luciferase reporter assay results revealed that NF2 is a downstream target of miR-146b-3p in PTC cells, as miR-146b-3p bound directly to the 3' untranslated region of NF2, thus reducing protein levels of NF2. Overexpression of merlin reversed the enhanced aggressive effects of miR-146b-3p. Conclusions: Overexpression of miR-146b-5p and miR-146b-3p is associated with PTC metastasis. MiR-146b-3p enhances cell invasion and metastasis more obviously than miR-146b-5p through the suppression of the NF2 gene. These findings suggest a potential diagnostic and therapeutic value of these miRNAs in PTC metastasis.

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MiR19b-3p promotes the growth and metastasis of colorectal cancer via directly targeting ITGB8.

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miR19b-3p promotes the growth and metastasis of colorectal cancer via directly targeting ITGB8.

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