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Original article
Upregulated immune checkpoint HHLA2 in clear cell renal cell carcinoma: a novel prognostic biomarker and potential therapeutic target
  1. Dongming Chen1,
  2. Wei Chen2,
  3. Yong Xu3,
  4. Meng Zhu1,
  5. Yi Xiao1,
  6. Yanhao Shen1,
  7. Shuai Zhu1,
  8. Changchun Cao1,
  9. Xianlin Xu1
  1. 1 Department of Urology, The Affiliated Sir Run Run Hospital of Nanjing Medical University, Nanjing, China
  2. 2 Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
  3. 3 Department of Nephrology, Huai’an Second People’s Hospital and the Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, China
  1. Correspondence to Changchun Cao, Department of Urology The Affiliated Sir Run Run Hospital of Nanjing Medical University Nanjing China ; caochangchun0424{at} and Dr Xianlin Xu, Department of Urology, The Affiliated Sir Run Run Hospital of Nanjing Medical University, Nanjing 211166, China; xianlinxu{at}


Background 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.

Methods 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.

Results 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.

Conclusion 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.

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

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  • DC, WC and YX contributed equally.

  • Contributors XX and CC contributed to the conception and design of the study. XX, WC, YX, CC and DC contributed to the provision of study materials or patients and manuscript revision. DC, MZ and YZ were responsible for the collection and assembly of data. MZ, SZ and YS were responsible for the data analysis and interpretation. DC, XX and CC wrote the manuscript. All authors approved the final manuscript.

  • Funding This work was supported by the Natural Science Foundation of Jiangsu Province (Grant no. BK20141161).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Approved by the Affiliated Sir Run Run Hospital of Nanjing Medical University.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Correction notice This article has been corrected since it was published Online First. A statement of equal contribution has been added.