[Retracted] HHLA2 Used as a Potential Prognostic and Immunological Biomarker and Correlated with Tumor Microenvironment in Pan‐Cancer

Abstract

Background. The role of HERV–H LTR-associating 2 (HHLA2) in cancer remains still unclear. This study analyzed the correlation between the prognosis and immune infiltrate function of HHLA2 in pan-cancers. Methods. HHLA2 expression in pan-cancers was analyzed using the databases of TCGA, GTEx, TIMER, GEPIA, UALCAN, and GSEA databases. Multiple bioinformatic methods were used to investigate the correlation of HHLA2 expression with survival, pathological stage, tumor mutation burden (TMB), microsatellite instability (MSI), tumor microenvironment (TME), immune cell infiltration, and immune checkpoint gene (ICG), and gene functional enrichment was performed by Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA). Results. HHLA2 was aberrantly expressed and was strongly correlated with positive or negative prognosis in multiple human cancers, which revealed that HHLA2 might play a vital role during cancer formation and development. Kaplan–Meier (KM) curves across cancers revealed that HHLA2 expression was correlated with overall survival (OS) in eight cancers, disease-specific survival (DSS) in seven cancers, disease-free interval (DFI) in four cancers, and progression-free interval (PFI) in nine cancers. Furthermore, HHLA2 expression was positively correlated with TMB in 6 cancer types and negatively associated with TMB in 7 cancer types, respectively. The former included ESCA, HNSC, KIRP, PAAD, PRAD, and PCPG; the latter contained COAD, LGG, LUAD, LUSC, THYM, THCA, and UCEC. Additionally, we found HHLA2 expression was negatively related to MSI in ACC, COAD, PAAD, and UCEC. More importantly, HHLA2 expression was remarkably correlated with the degree of tumor-infiltrating immune in many cancers, including B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells and strongly associated with immune checkpoint genes in 13 tumor types. Furthermore, KEGG pathway analyses indicated that HHLA2 could potentially impact cancer etiology or pathogenesis by functioning in amino sugar and nucleotide sugar metabolism, cytosolic DNA sensing pathway, and peroxisome pathways. Meanwhile, GSVA analysis results all indicate that HHLA2 was correlated with TSC/mTOR, RTK, RAS/MAPK, PI3K/AKT, EMT, DNA Damage Response, Cell Cycle, and Apoptosis pathways in various cancers. Conclusion. HHLA2 can function as a prognostic biomarker and correlate with tumor immunity in human pan-cancer due to its important role in tumorigenesis and immune infiltration, which provides new insight into developing new targeted treatments in cancers.

Overexpression and Role of HHLA2, a Novel Immune Checkpoint, in Colorectal Cancer

“…HHLA2 is a novel immune checkpoint molecule belonging to the B7 family of ligands and is widely expressed in cancer samples and participates in the growth and development of various cancers [ 13 , 17 ]. Our study found a significantly higher level of HHLA2 protein in tumors compared to healthy tissue, and 97% of tumors stained positive for HHLA2.…”

“…Upregulation of HHLA2 was also demonstrated in other studies considering colorectal cancer. Yang et al found out that there was an overexpression of HHLA2 mRNA in CRC tissues [ 13 ]. Wang et al concluded that due to its high expression, both at the mRNA and protein levels, HHLA2 may be a potential immunotherapeutic target for CRC patients [ 18 ].…”

“…It has been reported that HHLA2 contributes to complex functions in the tumor microenvironment [ 9 , 11 , 12 , 13 ]. However, the value of HHLA2 in colorectal cancer remains unknown and needs further investigation.…”

A pan-cancer analysis of Dyskeratosis congenita 1 (DKC1) as a prognostic biomarker

“…Reducing the incidence of cancer and improving cancer diagnosis were important ways to solve current health problems. Recently, pan-cancer analysis was applied to analysis DNA and RNA changes and tumor related genes associating with cancer occurrence, which have important implications for early cancer diagnosis and cancer treatment [23][24][25]. Pan-cancer analysis can identify commonalities and differences across different tumors to help cancer prevention and diagnosis strategies [26,27].…”

Retracted: HHLA2 Used as a Potential Prognostic and Immunological Biomarker and Correlated with Tumor Microenvironment in Pan-Cancer

“…This article has been retracted by Hindawi following an investigation undertaken by the publisher [ 1 ]. This investigation has uncovered evidence of one or more of the following indicators of systematic manipulation of the publication process: Discrepancies in scope Discrepancies in the description of the research reported Discrepancies between the availability of data and the research described Inappropriate citations Incoherent, meaningless and/or irrelevant content included in the article Manipulated or compromised peer review …”