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A lncRNA TCL6-miR-155 Interaction Regulates the Src-Akt-EMT Network to Mediate Kidney Cancer Progression and Metastasis.

ABSTRACT: Metastasis is the leading cause of mortality from kidney cancer, and understanding the underlying mechanism of this event will provide better strategies for its management. Here we investigated the biological, functional, and clinical significance of lncTCL6 and its interacting miR-155 in clear cell renal cell carcinoma (ccRCC). We employed a comprehensive approach to investigate the lncTCL6-miR-155-Src/Akt-mediated epithelial-to-mesenchymal transition (EMT) pathway as a novel regulatory mechanism in ccRCC progression. Expression analyses revealed that lncTCL6 is downregulated in ccRCC compared with normal tissues. Overexpression of lncTCL6 in ccRCC cell lines impaired their oncogenic functions, such as cell proliferation and migration/invasion, and induced cell-cycle arrest and apoptosis; conversely, depletion of lncTCL6 rescued these phenotypic effects. Furthermore, lncTCL6 directly interacted with miR-155. Unlike lncTCL6, miR-155 was overexpressed in ccRCC. Stable knockdown of miR-155 phenocopied the effects of lncTCL6 overexpression. Conversely, reconstitution of miR-155 and suppression of lncTCL6 in noncancerous renal cell HK2 induced tumorigenic characteristics. Patients with higher expression of lncTCL6 and lower expression of miR-155 had better survival probability. When overexpressed, lncTCL6 recruited STAU1 and mediated decay of Src mRNA, followed by a marked downregulation of an integrated network of Src target genes involved in migration, invasion, and EMT. However, the interaction between miR-155 and lncTCL6 attenuated the regulatory role of lncTCL6 on Src-mediated EMT. In conclusion, this study is the first report documenting the lncTCL6-miR155-Src/Akt/EMT network as a novel regulatory mechanism in aggressive ccRCC and a promising therapeutic target to inhibit renal cancer. SIGNIFICANCE: This study's investigation of noncoding RNA interactions in renal cell carcinoma identify miRNA-155-lncRNA TCL6-mediated regulation of the Src-Akt-EMT network as a novel mechanism of disease progression and metastasis.

SUBMITTER: Kulkarni P

PROVIDER: S-EPMC7969457 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Objective:To study the role of LncRNA PTTG3P in colorectal cancer (CRC) and the underlying mechanism. Patients and Methods:The expression level of LncRNA PTTG3P was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) in CRC cell lines and tumor tissues from 43 CRC patients, and the correlations between LncRNA PTTG3P expression and the clinicopathological indicators and prognosis of CRC patients were analyzed. Then, a PTTG3P knockdown model in CRC cell lines HCT-8 and HCT-116 was constructed. Finally, the relationship between LncRNA PTTG3P and microRNA-155-5p was explored through luciferase reporter experiments and recovery experiments. Results:qRT-PCR results showed that LncRNA PTTG3P was markedly up-regulated in CRC tumor tissues than that in adjacent tissues. Meanwhile, patients with high LncRNA PTTG3P expression had higher rates of lymph node metastasis and distant metastasis. In addition, cell functional experiments suggested that knocking down PTTG3P markedly reduced the migration abilities of CRC cells. Subsequently, bioinformatics analysis and luciferase reporter gene experiments suggested that LncRNA PTTG3P could directly bind to microRNA-155-5P. Analysis of CRC tissue samples showed that microRNA-155-5P expression was markedly reduced in CRC and was negatively correlated with LncRNA PTTG3P. Finally, the recovery experiments also suggested that there was a mutual regulation between LncRNA PTTG3P and microRNA-155-5P, and silencing microRNA-155-5P can reverse the inhibitory effect of knocking down PTTG3P on the malignant progression of CRC. Conclusion:In summary, LncRNA PTTG3P level was markedly increased in CRC, and was highly correlated to the incidence of lymph node metastasis and distant metastasis in CRC patients. In addition, LncRNA PTTG3P might promote the ability of CRC to invade and migrate by downregulating microRNA-155-5P. Therefore, dissecting the aberrant regulation of LncRNA PTTG3P/microRNA-155-5P may be valuable for early screening, guidance treatment, and recurrence detection of CRC.

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A lncRNA TCL6-miR-155 Interaction Regulates the Src-Akt-EMT Network to Mediate Kidney Cancer Progression and Metastasis.

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