CLEC11A expression as a prognostic biomarker in correlation to immune cells of gastric cancer.

Gastric cancer (GC) is a prevalent malignant cancer characterized by a poor survival rate. The C-type lectin domain family 11 member A (CLEC11A) is part of the C-type lectin superfamily, and its dysregulation has been implicated in the progression of several cancers. The specific role of CLEC11A and its association with immune infiltration in GC, however, remains unclear. In this study, we employed The Cancer Genome Atlas (TCGA) database, Gene Expression Omnibus (GEO) database, Tumor IMmune Estimation Resource (TIMER) database, Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, Kaplan-Meier plotter databases, gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and the CIBERSORT algorithm to investigate CLEC11A expression, its prognostic significance, its association with tumor immune infiltration, and gene function enrichment in GC. We conducted western blotting, Cell Counting Kit-8 (CCK-8), wound healing, and transwell assays to validate CLEC11A's function. We found that CLEC11A expression was significantly elevated in GC when compared to adjacent non-tumor tissues. Elevated CLEC11A expression was strongly associated with poor survival outcomes and advanced clinicopathological stages.  Moreover, heightened CLEC11A expression positively correlated with immunomodulators, chemokines, and the infiltration of immune cells, especially M2 macrophages, in GC. Additionally, CLEC11A silencing suppressed GC cells proliferation, migration and invasion in vitro. Our results elucidate the functions of CLEC11A in GC, suggesting its potential as a valuable prognostic biomarker and therapeutic target for GC immunotherapy.

Upregulated GPRC5A disrupting the Hippo pathway promotes the proliferation and migration of pancreatic cancer cells via the cAMP-CREB axis.

BACKGROUND: Pancreatic cancer has a high mortality rate worldwide, and is predicted to be third leading cause of death in the near future. However, the regulatory mechanisms that inhibit the progression of pancreatic cancer remain elusive. Currently, exploring the function and mechanisms of GPCRs (G-protein coupled receptors) is an important way to discover promising therapeutic targets for cancer. METHODS: GPRC5A expression was measured using real-time quantitative PCR, immunohistochemistry and western blot assays. Cell proliferation and migration were assessed using CCK-8, clone formation, wound-healing and transwell assays. A cytosolic/nuclear distribution experiment was used to detect the protein location transfer. A xenograft model of pancreatic cancer was established to explore the role of GPRC5A in vivo. RESULTS: GPRC5A expression was increased in pancreatic cancer, and disruption of GPRC5A expression inhibited tumor growth in vivo. Mechanistically, GPRC5A positively regulated the transcription of YAP1 through cAMP-CREB signaling. Moreover, we show that the proliferation and migration induced by GPRC5A in pancreatic cancer could be rescued by inhibiting YAP1 expression. CONCLUSIONS: GPRC5A interacts with the Hippo pathway to promote the progression of pancreatic cancer. These findings reveal an important crosstalk model and provide potential targets for pancreatic cancer therapy.

COMMD2 Upregulation Mediated by an ncRNA Axis Correlates With an Unfavorable Prognosis and Tumor Immune Infiltration in Liver Hepatocellular Carcinoma.

Liver hepatocellular carcinoma (LIHC) seriously endangers the health and quality of life of individuals worldwide. Increasing evidence has underscored that the copper metabolism MURR1 domain (COMMD) family plays important roles in tumorigenesis. However, the specific role, biological function, mechanism and prognostic value of COMMD2 and its correlation with immune cell infiltration in LIHC remain unknown. In this study, we first determined the expression and prognostic potential of COMMD2 in human tumors using The Cancer Genome Atlas (TCGA) data and identified COMMD2 as a potential oncogene in LIHC. High COMMD2 expression was associated with pathological tumor stage and metastasis. Subsequently, noncoding RNAs (ncRNAs) upregulating COMMD2 expression were identified by performing expression, correlation, and survival analyses in combination. The CRNDE/LINC00511/SNHG17/HCG18-miR-29c-3p axis was identified as the most likely ncRNA-associated pathway upstream of COMMD2 in LIHC. Next, the expression profiles of COMMD2 and ncRNAs were validated in LIHC tissues and adjacent normal tissues. Furthermore, COMMD2 was significantly positively correlated with tumor immune cell infiltration, immune cell biomarkers, and immune checkpoint molecule expression. Importantly, COMMD2 potentially influenced prognosis by regulating immune cell infiltration in LIHC. Finally, COMMD2 was knocked down in LIHC cell lines using siRNAs for functional assays in vitro, resulting in suppressed cell proliferation and migration. In summary, our findings showed that the ncRNA-mediated upregulation of COMMD2 was associated with an unfavorable prognosis correlated with immune cell infiltration in LIHC.

Identification of a Novel Survival-Related circRNA-miRNA-mRNA Regulatory Network Related to Immune Infiltration in Liver Hepatocellular Carcinoma.

Increasing studies have reported that circular RNAs (circRNAs) play critical roles in tumorigenesis and cancer progression. However, the underlying regulatory mechanisms of circRNA-related competing endogenous RNA (ceRNA) in liver hepatocellular carcinoma (LIHC) are still unclear. In the present study, we discovered dysregulated circRNAs through Gene Expression Omnibus (GEO) analysis and validated the expression of the top seven circRNAs with upregulated expression by qRT-PCR and Sanger sequencing. Then, the Cancer-Specific CircRNA Database (CSCD) was used to predict the downstream miRNAs of seven circRNAs, and expression and survival analyses through The Cancer Genome Atlas (TCGA) were performed to identify the key miRNA in LIHC. Thereafter, the hsa_circ_0017264-hsa-miR-195-5p subnetwork was successfully constructed. Subsequently, we predicted downstream target genes of hsa-miR-195-5p with TargetScan, miRDB, and mirtarbase and overlapped them with differentially expressed mRNAs to obtain 21 target genes. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to predict the biological and functional roles of these target genes. Finally, with Pearson correlation and prognostic value analysis, a survival-related hsa_circ_0017264-hsa-miR-195-5p-CHEK1/CDC25A/FOXK1 axis was established. Gene set enrichment analysis (GSEA) was performed to determine the function of CHEK1/CDC25A/FOXK1 in the ceRNA network. Moreover, immune infiltration analysis revealed that the ceRNA network was markedly associated with the levels of multiple immune cell infiltrates, immune cell biomarkers and immune checkpoints. Overall, the hsa_circ_0017264-hsa-miR-195-5p-CHEK1/CDC25A/FOXK1 network might provide novel insights into the potential mechanisms underlying LIHC onset and progression.

USP49 mediates tumor progression and poor prognosis through a YAP1-dependent feedback loop in gastric cancer.

The importance of the Hippo-Yes-associated protein 1 (YAP1) pathway in gastric carcinogenesis and metastasis has attracted considerable research attention; however, the regulatory network of YAP1 in gastric cancer (GC) is not completely understood. In this study, ubiquitin-specific peptidase 49 (USP49) was identified as a novel deubiquitinase of YAP1, knockdown of USP49 inhibited the proliferation, metastasis, chemoresistance, and peritoneal metastasis of GC cells. Overexpression of USP49 showed opposing biological effects. Moreover, USP49 was transcriptionally activated by the YAP1/TEAD4 complex, which formed a positive feedback loop with YAP1 to promote the malignant progression of GC cells. Finally, we collected tissue samples and clinical follow-up information from 482 GC patients. The results showed that USP49 expression was high in GC cells and positively correlated with the expression of YAP1 and its target genes, connective tissue growth factor (CTGF) and cysteine-rich angiogenic inducer 61 (CYR61). Survival and Cox regression analysis showed that high USP49 expression was associated with poor prognosis and was an independent prognostic factor. Moreover, patients with high USP49 and YAP1 expression had extremely short overall survival. The findings of this study reveal that the aberrant activation of the USP49/YAP1 positive feedback loop plays a critical role in the malignant progression of GC, thus providing potential novel prognostic factors and therapeutic targets for GC.

microRNA-128-3p inhibits CD4+ regulatory T cells enrichment by targeting interleukin 16 in gastric cancer.

Previous studies have confirmed that microRNA (miR)-128-3p is expressed at low levels in gastric cancer (GC), and low miR-128-3p expression promotes the growth of GC cells. However, whether the dysregulation of miR-128-3p expression affects tumor-infiltrating lymphocytes (TILs) and leads to immune escape remains unclear. In the present study, predictive bioinformatics approaches showed that miR-128-3p expression was inversely correlated with tumor-infiltrating lymphocyte enrichment. When CD4 + T cells and regulatory T cells (Tregs) were enriched, lower miR-128-3p expression was associated with worse overall survival. However, when numbers of CD8 + T cells were decreased, the upregulation of miR-128-3p expression had a favorable effect on GC prognosis. Dual-luciferase reporter assays and cell biology experiments revealed that interleukin 16 (IL16) was the target of miR-128-3p and was negatively regulated by miR-128-3p. In addition, GC cells were cocultured with T lymphocytes, and the subsequent flow cytometric analysis showed that overexpression of miR-128-3p in tumor cells decreased the percentages of CD4+ CD25+ Foxp3+ Tregs by downregulating IL16 expression in GC, whereas miR-128-3p inhibition had the opposite effect. Moreover, the recombinant IL16 reversed the effects of miR-128-3p overexpression, and a competitive antibody against the IL16 receptor CD4 also reversed the effects of miR-128-3p knockdown. These studies identified the mechanism by which the miR-128-3p/IL16 axis promotes the infiltration of CD4+ Tregs in GC, and this mechanism will be a promising therapeutic target in GC immunotherapy.

Correction to: Identification hub genes of consensus molecular subtype correlation with immune infiltration and predict prognosis in gastric cancer.

[This corrects the article DOI: 10.1007/s12672-021-00434-5.].

Identification hub genes of consensus molecular subtype correlation with immune infiltration and predict prognosis in gastric cancer.

Gastric cancer (GC) has a great fatality rate, meanwhile, there is still a lack of available biomarkers for prognosis. The goal of the research was to discover key and novel potential biomarkers for GC. We screened for the expression of significantly altered genes based on survival rates from two consensus molecular subtypes (CMS) of GC. Subsequently, functional enrichment analysis showed these genes involved in many cancers. And we picked 6 hub genes that could both secreted in the tumor microenvironment and expression enhanced in immune cells. Then, Kaplan Meier survival and expression detected in the tumor pathological stage were utilized to clarify the prognostic of these 6 hub genes. The results indicated that OGN, CHRDL2, C2orf40, THBS4, CHRDL1, and ANGPTL1, respectively, were significantly associated with poor OS in GC patients. And their expression increased with cancer advanced. Moreover, immune infiltration analysis displayed that those hub genes expression positively with M2 macrophage, CD8+ T Cell, most immune inhibitors, and majority immunostimulators. In summary, our results suggested that OGN, CHRDL2, C2orf40, THBS4, CHRDL1, and ANGPTL1 were all potential biomarkers for GC prognosis and might also be potential therapeutic targets for GC.