Pan-cancer analysis combined with experiments predicts CTHRC1 as a therapeutic target for human cancers

Peng, Dazhao; Cheng, Wei; Zhang, Xiaoyang; Li, Shenghui; Liang, Hao; Zheng, Xingyu; Jiang, Shulong; Han, Lei

doi:10.1186/s12935-021-02266-3

Cited by 25 publications

(18 citation statements)

References 64 publications

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“…The Human Protein Atlas (HPA) online website ( ) was used to analyze ALKBH5 in “Tissue Atlas”. The expression data of ALKBH5 gene in different human normal tissues were obtained ( 24 ). The row data source was TMM normalized.…”

Section: Methodsmentioning

confidence: 99%

Pan-Cancer Analysis Shows That ALKBH5 Is a Potential Prognostic and Immunotherapeutic Biomarker for Multiple Cancer Types Including Gliomas

et al. 2022

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BackgroundAlkB homolog 5 (ALKBH5) is a N6-methyladenosine (m6A) demethylase associated with the development, growth, and progression of multiple cancer types. However, the biological role of ALKBH5 has not been investigated in pan-cancer datasets. Therefore, in this study, comprehensive bioinformatics analysis of pan-cancer datasets was performed to determine the mechanisms through which ALKBH5 regulates tumorigenesis.MethodsOnline websites and databases such as NCBI, UCSC, CCLE, HPA, TIMER2, GEPIA2, cBioPortal, UALCAN, STRING, SangerBox, ImmuCellAl, xCell, and GenePattern were used to extract data of ALKBH5 in multiple cancers. The pan-cancer patient datasets were analyzed to determine the relationship between ALKBH5 expression, genetic alterations, methylation status, and tumor immunity. Targetscan, miRWalk, miRDB, miRabel, LncBase databases and Cytoscape tool were used to identify microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) that regulate expression of ALKBH5 and construct the lncRNA-miRNA-ALKBH5 network. In vitro CCK-8, wound healing, Transwell and M2 macrophage infiltration assays as well as in vivo xenograft animal experiments were performed to determine the biological functions of ALKBH5 in glioma cells.ResultsThe pan-cancer analysis showed that ALKBH5 was upregulated in several solid tumors. ALKBH5 expression significantly correlated with the prognosis of cancer patients. Genetic alterations including duplications and deep mutations of the ALKBH5 gene were identified in several cancer types. Alterations in the ALKBH5 gene correlated with tumor prognosis. GO and KEGG enrichment analyses showed that ALKBH5-related genes were enriched in the inflammatory, metabolic, and immune signaling pathways in glioma. ALKBH5 expression correlated with the expression of immune checkpoint (ICP) genes, and influenced sensitivity to immunotherapy. We constructed a lncRNA-miRNA network that regulates ALKBH5 expression in tumor development and progression. In vitro and in vivo experiments showed that ALKBH5 promoted proliferation, migration, and invasion of glioma cells and recruited the M2 macrophage to glioma cells.ConclusionsALKBH5 was overexpressed in multiple cancer types and promoted the development and progression of cancers through several mechanisms including regulation of the tumor-infiltration of immune cells. Our study shows that ALKBH5 is a promising prognostic and immunotherapeutic biomarker in some malignant tumors.

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Section: Methodsmentioning

confidence: 99%

Pan-Cancer Analysis Shows That ALKBH5 Is a Potential Prognostic and Immunotherapeutic Biomarker for Multiple Cancer Types Including Gliomas

et al. 2022

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“…Our previous studies showed that CTHRC1 was overexpressed in various cancer types and functions as an important oncogene that may promote tumorigenesis and development through different mechanisms including glioma [ 23 ]. Analysis of CTHRC1 expression in 41 glioma samples confirmed these results (Fig.…”

Section: Resultsmentioning

confidence: 99%

LncRNA HOXA11-AS promotes glioma malignant phenotypes and reduces its sensitivity to ROS via Tpl2-MEK1/2-ERK1/2 pathway

et al. 2022

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Our previous studies showed that dysregulation of the long noncoding RNA (lncRNA) HOXA11-AS plays an important role in the development of glioma. However, the molecular mechanism of HOXA11-AS in glioma remains largely unknown. In this study, we explore the molecular mechanisms underlying abnormal expression and biological function of HOXA11-AS for identifying novel therapeutic targets in glioma. The expression of HOXA11-AS, and the relationship between HOXA11-AS and the prognosis of glioma patients were analyzed using databases and glioma samples. Transcriptomics, proteomics, RIP, ChIRP, luciferase, and ChIP assays were used to explore its upstream and downstream targets in glioma. The role of HOXA11-AS in regulating the sensitivity of glioma cells to reactive oxygen species (ROS) was also investigated in vitro and in vivo. We found that HOXA11-AS was significantly upregulated in glioma, and was correlated with the poor prognosis of glioma patients. Ectopic expression of HOXA11-AS promoted the proliferation, migration, and invasion of glioma cells in vitro and in vivo. Mechanistically, HOXA11-AS acted as a molecular sponge for let-7b-5p in the cytoplasm, antagonizing its ability to repress the expression of CTHRC1, which activates the β-catenin/c-Myc pathway. In addition, c-Myc was involved in HOXA11-AS dysregulation via binding to its promoter region to form a self-activating loop. HOXA11-AS, functioned as a scaffold in the nucleus, also recruited transcription factor c-Jun to the Tpl2 promoter, which activates the Tpl2-MEK1/2-ERK1/2 pathway to promote ROS resistance in glioma. Importantly, HOXA11-AS knockdown could sensitize glioma cells to ROS. Above, oncogenic HOXA11-AS upregulates CTHRC1 expression as a ceRNA by adsorbing let-7b-5p, which activates c-Myc to regulate itself transcription. HOXA11-AS knockdown promotes ROS sensitivity in glioma cells by regulating the Tpl2-MEK1/2-ERK1/2 axis, demonstrating that HOXA11-AS may be translated to increase ROS sensitivity therapeutically.

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“…These studies have specifically implicated CTHRC1 with immune infiltration in Kidney and Brain cancers. Peng at al [ 38 ] reported that in addition to being upregulated in high-grade gliomas, CTHRC1 expression correlated with genes associated with the Wnt Signaling pathway (DVL3, DVL1, DVL2, ROR2, WNT3A, FZD6 and FZD5). Our study in evaluating 1027 matrisome genes across cancers, has identified a novel set of genes (MMP13, FNDC1, SFRP4 and ADAMTS16) that could work with CTHRC1 to regulate cancer progression.…”

Section: Discussionmentioning

confidence: 99%

A pan-cancer analysis of matrisome proteins reveals CTHRC1 and a related network as major ECM regulators across cancers

2022

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The extracellular matrix in the tumour microenvironment can regulate cancer cell growth and progression. A pan-cancer analysis of TCGA data from 30 cancer types, identified the top 5% of matrisome genes with amplifications or deletions in their copy number, that affect their expression and cancer survival. A similar analysis of matrisome genes in individual cancers identified CTHRC1 to be significantly altered. CTHRC1, a regulator of collagen synthesis, was identified as the most prominently upregulated matrisome gene of interest across cancers. Differential gene expression analysis identified 19 genes whose expression is increased with CTHRC1. STRING analysis of these genes classified them as ‘extracellular’, involved most prominently in ECM organization and cell adhesion. KEGG analysis showed their involvement in ECM-receptor and growth factor signalling. Cytohubba analysis of these genes revealed 13 hub genes, of which MMP13, POSTN, SFRP4, ADAMTS16 and FNDC1 were significantly altered in their expression with CTHRC1 and seen to affect survival across cancers. This could in part be mediated by their overlapping roles in regulating ECM (collagen or fibronectin) expression and organisation. In breast cancer tumour samples CTHRC1 protein levels are significantly upregulated with POSTN and MMP13, further supporting the need to evaluate their crosstalk in cancers.

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Pan-cancer analysis combined with experiments predicts CTHRC1 as a therapeutic target for human cancers

Cited by 25 publications

References 64 publications

Pan-Cancer Analysis Shows That ALKBH5 Is a Potential Prognostic and Immunotherapeutic Biomarker for Multiple Cancer Types Including Gliomas

Pan-Cancer Analysis Shows That ALKBH5 Is a Potential Prognostic and Immunotherapeutic Biomarker for Multiple Cancer Types Including Gliomas

LncRNA HOXA11-AS promotes glioma malignant phenotypes and reduces its sensitivity to ROS via Tpl2-MEK1/2-ERK1/2 pathway

A pan-cancer analysis of matrisome proteins reveals CTHRC1 and a related network as major ECM regulators across cancers

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