Abstract
BackgroundIncreasing evidence has indicated that long noncoding RNAs (lncRNAs) are crucial regulators affecting the progression of human cancers. Recently, lncRNA downregulated in liver cancer stem cells (lnc-DILC) was identified to function as a tumor suppressor inhibiting the tumorigenesis and metastasis in liver cancer and colorectal cancer. However, to date, little is known about the functional roles of lnc-DILC in modulating malignant phenotypes of clear cell renal cell carcinoma (ccRCC) cells.Methodslnc-DILC expression in human ccRCC tissues was detected by qRT-PCR. Overexpression and knockdown experiments were carried out to determine the effects of lnc-DILC on ccRCC cell proliferation, migration and invasion. To reveal the underlying mechanisms of lnc-DILC functions in ccRCC cells. RNA immunoprecipitation, RNA pull-down, in vivo ubiquitination, co-immunoprecipitation and western blot assays were performed.ResultsHere, we identified that lnc-DILC levels were dramatically downregulated in ccRCC tissues. Loss of lnc-DILC expression was correlated with larger tumor size, advanced tumor grade and lymph node metastasis, and also predicted worse prognosis in patients with ccRCC. Functionally, knockdown and overexpression experiments demonstrated that lnc-DILC inhibited cell proliferation, migration and invasion in ccRCC cells. Mechanistic investigation revealed that lnc-DILC bound to tumor suppressor PTEN and suppressed its degradation. lnc-DILC repressed the PTEN ubiquitination through blocking the interaction between PTEN and E3 ubiquitin ligase WWP2 and recruiting the deubiquitinase USP11 to PTEN. Moreover, we demonstrated that PTEN–AKT signaling was crucial for lnc-DILC-mediated suppressive effects.ConclusionsIn summary, our research revealed a novel mechanism by which lnc-DILC regulates PTEN stability via WWP2 and USP11, and shed light on potential therapeutic strategies by the restoration of lnc-DILC expression in patients with ccRCC.
Highlights
Increasing evidence has indicated that long noncoding RNAs are crucial regulators affecting the progression of human cancers
To investigate the clinical significance of aberrant expression of lnc-DILC, the patients were divided into high-expression and lowexpression groups according to the median value of lncDILC expression in clear cell renal cell carcinoma (ccRCC) tissues
We evaluated the prognostic value of lnc-DILC expression in ccRCC patients through Kaplan–Meier method, and the results demonstrated high-expression group had a better overall survival, as compared to low-expression group (Fig. 1b)
Summary
Increasing evidence has indicated that long noncoding RNAs (lncRNAs) are crucial regulators affecting the progression of human cancers. To date, little is known about the functional roles of lnc-DILC in modulating malignant phenotypes of clear cell renal cell carcinoma (ccRCC) cells. Clear cell RCC (ccRCC) is the most common subtype, Long noncoding RNAs (lncRNAs) are a group of transcripts more than 200 nucleotides in length and not. Mounting evidence indicated that lncRNAs exert crucial regulatory functions. LncRNAs exert their regulatory function via association with other molecules, such as mRNAs, microRNAs and proteins. LncRNA HCAL associates with miR-196a/b and blocks miR-196a/bmediated LAPTM4B suppression, which enhances growth and metastasis in liver cancer [11]. Only a few tumorsuppressive lncRNAs and the exact mechanisms have been well investigated
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