Overexpression of HHLA2 in human clear cell renal cell carcinoma is significantly associated with poor survival of the patients
Abstract Background It is well known that human clear cell renal cell carcinoma (ccRCC) is a highly immunogenic and chemo-resistant tumor. Recently, emerging data suggest that the immune checkpoint blockade therapy is an important breakthrough in the treatment against ccRCC. HHLA2, a recently report...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-04-01
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| Series: | Cancer Cell International |
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| Online Access: | http://link.springer.com/article/10.1186/s12935-019-0813-2 |
| _version_ | 1811288384269713408 |
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| author | Lujun Chen Dawei Zhu Jun Feng You Zhou Qi Wang Huijing Feng Junping Zhang Jingting Jiang |
| author_facet | Lujun Chen Dawei Zhu Jun Feng You Zhou Qi Wang Huijing Feng Junping Zhang Jingting Jiang |
| author_sort | Lujun Chen |
| collection | DOAJ |
| description | Abstract Background It is well known that human clear cell renal cell carcinoma (ccRCC) is a highly immunogenic and chemo-resistant tumor. Recently, emerging data suggest that the immune checkpoint blockade therapy is an important breakthrough in the treatment against ccRCC. HHLA2, a recently reported member of B7 family, is uniquely expressed in humans but not in mice, and it plays an important role in the functional inhibition of CD4 and CD8 T cells. Herein, we aimed to study the clinical implications of HHLA2 expression in human ccRCC and its potential regulatory role in the biological functions of the cancer cells. Methods In the present study, we examined HHLA2 expression in human ccRCC tissues and analyzed the clinical implications as well as prognostic value. The intervention of HHLA2 in human ccRCC cell lines ACHN and 786-O was performed and its effect on the cellular function of the cells was also analyzed. We also identified the differentially expressed genes upon HHLA2 knockdown in ccRCC cell lines by using gene microarray analysis. Results We found that higher HHLA2 mRNA expression level in human ccRCC tissues compared with that in adjacent normal tissues based on TCGA data, and the HHLA2 expression at mRNA level was positively and significantly correlated with PD-L1, PD-L2, B7-H6, but negatively and significantly correlated with B7-H3. Moreover, our immunohistochemistry study showed that the staining intensity of HHLA2 in human ccRCC tissues was significantly higher than that in the adjacent normal tissues, and the overall survival rate of ccRCC patients with higher HHLA2 expression was significantly poorer than that of the patients with lower HHLA2 expression. Higher expression of HHLA2 in ccRCC tissues was positively and significantly associated with larger tumor size and advanced TNM stage. The COX model revealed that the parameters including patient’s age, TNM stage and HHLA2 expression level could be used as the independent risk factors respectively for the prognostic prediction of the patients. Our cellular study showed that upon knockdown of HHLA2 expression in human ccRCC cell lines, the cell viability, the migration and the invasion ability were significantly inhibited, while the cell cycle arrest at G1 phase was induced and the expressions of Cyclin D1, c-Myc and Cyclin E1 were decreased. In addition, according to the microarray data, the expressions of epithelia-to-mesenchymal transition markers, such as E-cadherin, N-cadherin and Vimentin, were significantly changed after knockdown of HHLA2 expression. Conclusions Our findings indicated that HHLA2 was involved in the progression of human ccRCC and could be used as an important prognostic predictor for this malignancy. |
| first_indexed | 2024-04-13T03:35:11Z |
| format | Article |
| id | doaj.art-c7c7005921314db680fe6e86edab185a |
| institution | Directory Open Access Journal |
| issn | 1475-2867 |
| language | English |
| last_indexed | 2024-04-13T03:35:11Z |
| publishDate | 2019-04-01 |
| publisher | BMC |
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| series | Cancer Cell International |
| spelling | doaj.art-c7c7005921314db680fe6e86edab185a2022-12-22T03:04:20ZengBMCCancer Cell International1475-28672019-04-0119111210.1186/s12935-019-0813-2Overexpression of HHLA2 in human clear cell renal cell carcinoma is significantly associated with poor survival of the patientsLujun Chen0Dawei Zhu1Jun Feng2You Zhou3Qi Wang4Huijing Feng5Junping Zhang6Jingting Jiang7Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow UniversityDepartment of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow UniversityDepartment of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow UniversityDepartment of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow UniversityDepartment of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow UniversityDepartment of Oncology, Shanxi Academy of Medical Sciences, Shanxi Dayi HospitalDepartment of Oncology, Shanxi Academy of Medical Sciences, Shanxi Dayi HospitalDepartment of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow UniversityAbstract Background It is well known that human clear cell renal cell carcinoma (ccRCC) is a highly immunogenic and chemo-resistant tumor. Recently, emerging data suggest that the immune checkpoint blockade therapy is an important breakthrough in the treatment against ccRCC. HHLA2, a recently reported member of B7 family, is uniquely expressed in humans but not in mice, and it plays an important role in the functional inhibition of CD4 and CD8 T cells. Herein, we aimed to study the clinical implications of HHLA2 expression in human ccRCC and its potential regulatory role in the biological functions of the cancer cells. Methods In the present study, we examined HHLA2 expression in human ccRCC tissues and analyzed the clinical implications as well as prognostic value. The intervention of HHLA2 in human ccRCC cell lines ACHN and 786-O was performed and its effect on the cellular function of the cells was also analyzed. We also identified the differentially expressed genes upon HHLA2 knockdown in ccRCC cell lines by using gene microarray analysis. Results We found that higher HHLA2 mRNA expression level in human ccRCC tissues compared with that in adjacent normal tissues based on TCGA data, and the HHLA2 expression at mRNA level was positively and significantly correlated with PD-L1, PD-L2, B7-H6, but negatively and significantly correlated with B7-H3. Moreover, our immunohistochemistry study showed that the staining intensity of HHLA2 in human ccRCC tissues was significantly higher than that in the adjacent normal tissues, and the overall survival rate of ccRCC patients with higher HHLA2 expression was significantly poorer than that of the patients with lower HHLA2 expression. Higher expression of HHLA2 in ccRCC tissues was positively and significantly associated with larger tumor size and advanced TNM stage. The COX model revealed that the parameters including patient’s age, TNM stage and HHLA2 expression level could be used as the independent risk factors respectively for the prognostic prediction of the patients. Our cellular study showed that upon knockdown of HHLA2 expression in human ccRCC cell lines, the cell viability, the migration and the invasion ability were significantly inhibited, while the cell cycle arrest at G1 phase was induced and the expressions of Cyclin D1, c-Myc and Cyclin E1 were decreased. In addition, according to the microarray data, the expressions of epithelia-to-mesenchymal transition markers, such as E-cadherin, N-cadherin and Vimentin, were significantly changed after knockdown of HHLA2 expression. Conclusions Our findings indicated that HHLA2 was involved in the progression of human ccRCC and could be used as an important prognostic predictor for this malignancy.http://link.springer.com/article/10.1186/s12935-019-0813-2HHLA2Clear cell renal cell carcinomaPrognosisEpithelial-to-mesenchymal transition |
| spellingShingle | Lujun Chen Dawei Zhu Jun Feng You Zhou Qi Wang Huijing Feng Junping Zhang Jingting Jiang Overexpression of HHLA2 in human clear cell renal cell carcinoma is significantly associated with poor survival of the patients Cancer Cell International HHLA2 Clear cell renal cell carcinoma Prognosis Epithelial-to-mesenchymal transition |
| title | Overexpression of HHLA2 in human clear cell renal cell carcinoma is significantly associated with poor survival of the patients |
| title_full | Overexpression of HHLA2 in human clear cell renal cell carcinoma is significantly associated with poor survival of the patients |
| title_fullStr | Overexpression of HHLA2 in human clear cell renal cell carcinoma is significantly associated with poor survival of the patients |
| title_full_unstemmed | Overexpression of HHLA2 in human clear cell renal cell carcinoma is significantly associated with poor survival of the patients |
| title_short | Overexpression of HHLA2 in human clear cell renal cell carcinoma is significantly associated with poor survival of the patients |
| title_sort | overexpression of hhla2 in human clear cell renal cell carcinoma is significantly associated with poor survival of the patients |
| topic | HHLA2 Clear cell renal cell carcinoma Prognosis Epithelial-to-mesenchymal transition |
| url | http://link.springer.com/article/10.1186/s12935-019-0813-2 |
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