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J Med Genet. 2019 Jan;56(1):43-49. doi: 10.1136/jmedgenet-2018-105454. Epub 2018 Jul 2.

Upregulated immune checkpoint HHLA2 in clear cell renal cell carcinoma: a novel prognostic biomarker and potential therapeutic target.

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Department of Urology, The Affiliated Sir Run Run Hospital of Nanjing Medical University, Nanjing, China.
Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Nephrology, Huai'an Second People's Hospital and the Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, China.
Contributed equally



Clear cell renal cell carcinoma (ccRCC) is a malignant urogenital cancer with high mortality; however, current progress in understanding its molecular mechanism and predicting clinical treatment outcome is limited. Therefore, this study is to evaluate the clinical significance of immune inhibitory molecular human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) in ccRCC prognosis and transcriptional regulatory network.


Expression of HHLA2 in ccRCC was examined by an online database platform ONCOMINE. The ONCOMINE result was independently validated by qRT-PCR and immunohistochemistry. Kaplan-Meier survival was generated using IBM SPSS Statistics V.22. ccRCC tissues cells with high HHLA2 were sorted and subjected to microarray transcriptional profiling and analysis.


It was shown that expression of HHLA2 was statistically significantly increased in ccRCC tissues compared with normal renal tissues at both transcriptional and protein level. Moreover, the expression of HHLA2 was closely correlated with multiple clinicopathological features including tumour size, clinical stage and histological grade. High HHLA2 expression was associated with poor overall survival and clinical outcome. Comprehensive microarray analysis further identified thousands of HHLA2 targets including mRNA, long non-coding RNA and circular RNA that might function in various biological processes, especially, immune response.


Increased HHLA2 expression was observed in ccRCC tumour tissue, which leads to a remarkable shorter overall survival and poorer prognosis. Together with other molecular evidence, we have demonstrated that HHLA2 could be a potential prognostic biomarker for ccRCC.


Hhla2; Mrna; circrna; clear cell renal cell carcinoma; lncrna

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