LncRNA TP73-AS1 Promotes Cell Proliferation and Inhibits Cell Apoptosis in Clear Cell Renal Cell Carcinoma Through Repressing KISS1 Expression and Inactivation of PI3K/Akt/mTOR Signaling Pathway.

Abstract

BACKGROUND/AIMS:

Emerging evidence suggests that long non-coding RNAs (lncRNAs) play a vital regulatory role in the pathogenesis and progression of renal cell carcinoma (RCC). We aim to determine lncRNA profiles in clear cell RCC (ccRCC) and investigate key lncRNAs involved in ccRCC tumorigenesis and progression.

METHODS:

RNA sequencing technique and qPCR were used to determine the candidate lncRNAs in ccRCC tissues. The correlations between lncRNA P73 antisense RNA 1T (TP73-AS1) levels and survival outcomes were analyzed to elucidate its clinical significance. The underlying mechanisms of TP73-AS1 in ccRCC were analyzed through in vitro functional assays.

RESULTS:

We found TP73-AS1 was upregulated in 40 ccRCC tissues compared with adjacent normal renal tissues and increased TP73-AS1 was correlated to aggressive clinicopathologic features and unfavorable prognosis. Knockdown of TP73-AS1 suppressed cell proliferation, invasion and induced cell apoptosis. We also identified KISS-1 metastasis-suppressor (KISS1) was significantly upregulated in TP73-AS1 knockdown cells. Further, we revealed that TP73-AS1 suppressed KISS1 expression through the interaction with Enhancer of zeste homolog 2 (EZH2) and the specific binding to KISS1 gene promoter region. Knockdown of KISS1 partly reversed TP73-AS1 knockdown-induced inhibition of cell proliferation and promotion of apoptosis. We further determined that TP73-AS1 knockdown activated PI3K/Akt/mTOR signaling pathway, while overexpression of TP73-AS1 induced inhibition of PI3K/Akt/mTOR pathway and these effects could be partly abolished by overexpression of KISS1.

CONCLUSION:

In conclusion, we identified that TP73-AS1 as an oncogenic lncRNA in the development of ccRCC and a potential target for human renal carcinoma treatment.

• Authors: Guanghua Liu, Xin Zhao, Jingmin Zhou, Xiangming Cheng, Zixing Ye, Zhigang Ji
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 48 Issue 1 Pg. 371-384 ( 2018) ISSN: 1421-9778 [Electronic] Germany
• PMID: 30016766 (Publication Type: Journal Article)
• Copyright: © 2018 The Author(s). Published by S. Karger AG, Basel.

Chemical References

• KISS1 protein, human
• Kisspeptins
• RNA, Long Noncoding
• RNA, Small Interfering
• long non-coding RNA KIAA0495, human
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Apoptosis
• Carcinoma, Renal Cell (metabolism, mortality, pathology)
• Cell Cycle Checkpoints
• Cell Line, Tumor
• Cell Proliferation
• Female
• Humans
• Kaplan-Meier Estimate
• Kidney Neoplasms (metabolism, mortality, pathology)
• Kisspeptins (genetics, metabolism)
• Male
• Middle Aged
• Phosphatidylinositol 3-Kinases (metabolism)
• Promoter Regions, Genetic
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA Interference
• RNA, Long Noncoding (antagonists & inhibitors, genetics, metabolism)
• RNA, Small Interfering (metabolism)
• Signal Transduction
• TOR Serine-Threonine Kinases (metabolism)