CXCL2/10/12/14 are prognostic biomarkers and correlated with immune infiltration in hepatocellular carcinoma.

BACKGROUND: C-x-C motif chemokine ligands (CXCLs) are critical regulators of cancer immunity and angiogenesis, which affect disease progression and treatment responses. The character of each CXCL in the prognosis and immune infiltration of hepatocellular carcinoma (HCC) patients is unclear yet. METHODS: Differentially expressed CXCLs between HCC and normal control were screened by Oncomine and GEPIA2. Genetic alternations of CXCLs in HCC were analyzed by cBioPortal. Clinicopathological relevance of CXCLs in HCC patients was analyzed using UALCAN. The prognostic value of CXCLs was evaluated using univariate and multivariate analyses. Correlations of CXCLs' expression with immune infiltration, chemokines and their receptors were assessed integrating TIMER, TISIDB, and GEPIA2. The co-expressed genes of CXCLs were discovered, and functional enrichment analysis was performed for them. RESULTS: CXCL9/10 was significantly higher expressed while CXCL2/12/14 was lower expressed in HCC than normal tissues, but they didn't show significant clinicopathological relevance in HCC patients. High-expression of CXCL2/10/12/14 indicated favorable outcomes of HCC patients. The expression of CXCL9/10/12/14 was significantly positively correlated with not only the infiltration and biomarkers' expression of various tumor-infiltrating immune cells but also the abundance of chemokines and their receptors. The co-expressed genes of the five CXCLs were extracellular components and regulated immune or inflammatory responses and signaling pathways of chemokine, Toll-like receptor and tumor necrosis factor might be involved. CONCLUSION: The present study proposed CXCL2/10/12/14 might predict outcomes of HCC patients and were extensively related with the immune microenvironment in HCC. It would be a prospective therapeutic strategy for HCC to enhance effective immunity surveillance through intervening in these CXCLs.

Human Gastric Cancer Stem Cell (GCSC) Markers Are Prognostic Factors Correlated With Immune Infiltration of Gastric Cancer.

The prognosis of patients with gastric cancer (GC) is still unsatisfying. Numerous markers of gastric cancer stem cells (GCSCs) have been identified and were thought to be related to cancer aggressiveness. However, the roles of GCSC markers in GC patients' prognosis and immune infiltration remain unknown. Expression of GCSC markers was analyzed using Oncomine and Gene Expression Profiling Interactive Analysis (GEPIA). Their associations with clinicopathological parameters were analyzed using UALCAN and LinkedOmics. Alternations and protein expression of GCSC markers were analyzed by cBioPortal and the Human Protein Atlas databases, respectively. The prognostic significance of GCSC markers was evaluated using Kaplan-Meier plotter. Correlations between the expression of GCSC markers and immune infiltration along with biomarkers of tumor-infiltrating immune cells (TIICs) were assessed combined Tumor Immune Estimation Resource and GEPIA. GeneMANIA was used to discover the interactive genes of GCSC markers, and enrichment analysis was performed using Database for Annotation, Visualization, and Integrated Discovery server. We identified six GCSC markers significantly up-expressed in GC, compared with normal stomach tissues. Among them, the overexpression of ICAM1, THY1, and CXCR4 significantly indicated adverse, while EPCAM indicated beneficial clinicopathological features of GC patients. The up-regulation of CXCR4 showed unfavorable prognostic significance, whereas EPCAM and TFRC showed the opposite. The six GCSC markers were all correlated with the infiltration and activation of distinct TIICs. Especially, ICAM1, THY1, and CXCR4 showed strongly positive correlations with tumor-associated macrophages. Besides, chemokine, Toll-like receptor, NF-kappa B, and HIF-1 signaling pathways might be involved in the regulation of GCSC markers on cancer development. This study proposed that GCSC markers might be promising targets of GC treatment to weaken cancer stem-like properties and strengthen anticancer immunity.

Identification of prognostic biomarkers associated with the occurrence of portal vein tumor thrombus in hepatocellular carcinoma.

The occurrence of portal vein tumor thrombus (PVTT) is strongly correlated to the staging and poor prognosis of hepatocellular carcinoma (HCC) patients. However, the mechanisms of PVTT formation remain unclear. This study aimed to investigate differentially expressed genes (DEGs) between primary tumor (PT) and PVTT tissues and comprehensively explored the underlying mechanisms of PVTT formation. The DEGs between PT and paired PVTT tissues were analyzed using transcriptional data from the Gene Expression Omnibus (GEO) database. The expression, clinical relevance, prognostic significance, genetic alternations, DNA methylation, correlations with immune infiltration, co-expression correlations, and functional enrichment analysis of the DEGs were explored using multiple databases. As result, 12 DEGs were commonly down-expressed in PVTT compared with PT tissues among three datasets. The expression of DCN, CCL21, IGJ, CXCL14, FCN3, LAMA2, and NPY1R was progressively decreased from normal liver, PT, to PVTT tissues, whose up-expression associated with favorable survivals of HCC patients. The genetic alternations and DNA methylation of the DEGs frequently occurred, and several methylated CpG sites of the DEGs significantly correlated with outcomes of HCC patients. The immune infiltration in the tumor microenvironment of HCC was correlated with the expression level of the DEGs. Besides, the DEGs and their co-expressive genes participated in the biological processes of extracellular matrix (ECM) organization and focal adhesion. In summary, this study indicated the dysregulation of ECM and focal adhesion might contribute to the formation of PVTT. And the above seven genes might serve as potential biomarkers of PVTT occurrence and prognosis of HCC patients.