H Long Terminal Repeat-Associating 2 (HHLA2) is a Biomarker of Advanced Stage Hepatocellular Carcinoma and Promotes Tumor Cell Development In Vitro

Luo, Moulun; Xiong, Yao; Lin, Yan; Liang, Rong; Li, Yongqiang; Ge, Lianying

doi:10.12659/msm.930215

Cited by 14 publications

(19 citation statements)

References 18 publications

(19 reference statements)

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“…This is consistent with another study that over-expression of HHLA2 is a protective factor for KIRC (kidney renal clear cell carcinoma) patients [22]. In Luo's study, HHLA2 was also reported to be overexpressed in HCC, compared with normal liver tissue, the expression of HHLA2 was associated with poor prognosis of HCC patients [23,24]. But in another HCC study, Liao et al indicated that HHLA2 is frequently expressed in HCC, and positive HHLA2 correlates with higher CD8 + cell density and favorable prognosis [25].…”

Section: Introductionsupporting

confidence: 88%

The association of HHLA2 and PD-L1 expression with prognosis and immune microenvironment in hepatocellular carcinoma

Wang

Chen

Yang

et al. 2022

Preprint

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Background HHLA2, a newly discovered B7 family member, is widely expressed in numerous tumors and regulates the immune microenvironment. However, its prognostic value remains controversial, and the roles of HHLA2 in hepatocellular carcinoma (HCC) are unclear. In this study, we aimed to investigate the expression patterns of HHLA2 and PD-L1 in HCC and elaborate their relationship with TILs (tumor-infiltrating lymphocytes) and the prognosis of patients with HCC. Methods HHLA2 and PD-L1 expression were evaluated through immunohistochemistry (IHC) and analyzed in relation to clinicopathological characteristics in cancer tissues from HCC cases (n = 547). When membranous or cytoplasmatic expression of PD-L1 > = 1% was considered a positive expression. The percentage (%) and quantification (per mm2) of TILs were evaluated by hematoxylin and eosin staining (HE). The quantification of CD3+, CD4 + and CD8 + TILs (per mm2) was evaluated by IHC. Results The positive rates of HHLA2 were comparable with those of PD-L1 in HCC tissues according to immunohistochemistry score. HHLA2-positive expression was significantly associated with old age, low serum AFP level and well tumor differentiation, and indicated a better overall survival (OS). Besides, HHLA2 expression was significantly associated with a low density of stromal TILs. However, PD-L1 expression on TC (Tumor cells) was significantly associated with a high density of stromal TILs, CD3 + and CD8 + TILs, similarly, PD-L1 expression on IC (Inflammatory cells) were also correlated with high density of stromal TILs, CD3+, CD4 + and CD8 + TILs. Notably, a new immune classification, based on HHLA2/PD-L1, successfully stratified OS, and patients with HHLA2(+)/PD-L1(-) status had the longest survival. Conclusion HHLA2 has a critical impact on the immune microenvironment and can be used as an independent prognostic factor for HCC. Combined the expression of HHLA2 and PD-L1 can be used as a new classification to stratify the risk of progression and death for patients with HCC. Our study may provide evidence for improving responses to immunotherapy-included comprehensive treatment for HCC in the future.

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Section: Introductionsupporting

confidence: 88%

The association of HHLA2 and PD-L1 expression with prognosis and immune microenvironment in hepatocellular carcinoma

Wang

Chen

Yang

et al. 2022

Preprint

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“…36–38 In our previously published work, we found that HHLA2 was highly expressed in HCC tissues, and was correlated with development and progression in HepG2 cells. 39 We used the LinkOmics online database to analyze pathways in HCC that potentially involve HHLA2. We identified three genes closely related to HHLA2: TFF2, FABP6, and PPP1R14D.…”

Section: Discussionmentioning

confidence: 99%

Clinical Significance of the HHLA2 Protein in Hepatocellular Carcinoma and the Tumor Microenvironment

Luo¹,

Lin²,

Liang³

et al. 2021

JIR

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Background The protein “human endogenous retrovirus H long terminal repeat-associating 2” (HHLA2), a member of the B7 family, has been linked to cancer progression and immune responses. However, its functional role in hepatocellular carcinoma (HCC) remains unknown. Methods Bioinformatics was used to examine the potential roles of HHLA2 in HCC and the molecular pathways involved. Expression of HHLA2 and PD-L1 as well as the density of tumor-infiltrating lymphocytes (TILs) in tumoral areas were evaluated by immunohistochemistry and hematoxylin-eosin staining of 202 resected human HCC samples. Potential correlations of HHLA2 expression with pathological characteristics or prognosis of HCC patients were explored. Different types of immune microenvironment in HCC were defined based on HHLA2 expression and TIL density. Results High HHLA2 levels in HCC correlated with more advanced clinical cancer stage ( P = 0.040), multiple tumors ( P = 0.044), poor tumor differentiation ( P = 0.048), microvascular invasion ( P = 0.011) and hepatic capsule invasion ( P = 0.047). HHLA2 levels correlated significantly with density of TILs, but not with PD-L1 levels. High HHLA2 levels were associated with worse prognosis. Intermediate and high TIL densities were independent predictors of better prognosis. Tumor microenvironments with type I (HHLA2 - high TILs +) or type IV (HHLA2 - low TILs +) were associated with better prognosis. Conclusion HHLA2 level can independently predict worse prognosis and affect the tumor microenvironment in HCC, which may help guide immunotherapy against the cancer.

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“…A similar upregulation of HHLA2 was observed in hepatocellular carcinoma, and the knockdown of HHLA2 increased cell adhesion, accelerated cell apoptosis, resulted in cell arrest and suppressed cellular processes. 22 The overexpression of HHLA2 inhibited cell proliferation of ovarian cancer. 19 The observed promoted effect of HHLA2 on PTC cells provides a view that the inhibition of HHLA2 might be a novel therapeutic strategy of PTC treatment.…”

Section: Discussionmentioning

confidence: 99%

Human Endogenous Retrovirus-H Long Terminal Repeat-Associating Protein 2 Possesses Prognostic Significance and Promotes Progression of Papillary Thyroid Cancer

Niu¹,

Huang²,

Dong³

et al. 2022

IJGM

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Identification of novel biomarkers could benefit the clinical therapy and management of papillary thyroid carcinoma (PTC). Human endogenous retrovirus long terminal repeat-associating protein 2 (HHLA2) has been reported to play roles in the development of various cancers. The clinical significance and biological function of HHLA2 in PTC were investigated. Patients and Methods:The expression level of HHLA2 was evaluated in PTC tissues (from 107 PTC patients) and cell lines (TPC-1, IHH-4, CGTH-W3, and MDA-T32 cells) by RT-qPCR. The clinical significance of HHLA2 was estimated with a series of statistical analyses. The biological function of HHLA2 was assessed with the CCK8 assay and transwell assay. Results: HHLA2 was upregulated in PTC compared with the normal samples and was associated with the positive lymph node metastasis and advanced TNM stage of PTC patients. HHLA2 was an independent prognostic factor associated with the poor survival of PTC patients. Additionally, HHLA2 functioned as a tumor promoter that enhanced the progression of PTC cells. Conclusion: HHLA2 could serve as a prognostic biomarker and tumor promoter in PTC, providing a novel therapeutic target of PTC.

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H Long Terminal Repeat-Associating 2 (HHLA2) is a Biomarker of Advanced Stage Hepatocellular Carcinoma and Promotes Tumor Cell Development In Vitro

Cited by 14 publications

References 18 publications

The association of HHLA2 and PD-L1 expression with prognosis and immune microenvironment in hepatocellular carcinoma

The association of HHLA2 and PD-L1 expression with prognosis and immune microenvironment in hepatocellular carcinoma

Clinical Significance of the HHLA2 Protein in Hepatocellular Carcinoma and the Tumor Microenvironment

Human Endogenous Retrovirus-H Long Terminal Repeat-Associating Protein 2 Possesses Prognostic Significance and Promotes Progression of Papillary Thyroid Cancer

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