CTHRC1 promotes liver metastasis by reshaping infiltrated macrophages through physical interactions with TGF-β receptors in colorectal cancer

Zhang, Xueli; Hu, Li-Peng; Yang, Qin; Qin, Weiting; Wang, Xu; Xu, Chunjie; Tian, Guang-Ang; Yang, Xiaomei; Yao, Lishuang; Zhu, Lei; Nie, Hui-Zhen; Li, Qing; Xu, Qing; Zhang, Zhigang; Li, Jun; Wang, Yahui; Jiang, Shu-Heng

doi:10.1038/s41388-021-01827-0

Cited by 49 publications

(40 citation statements)

References 54 publications

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“…S5 and S6). Taken together, these results reveal that CTHRC1 is an oncogene and an important prognostic factor in some tumors, which is mutually corroborated by recent publications [ 16 , 47 – 51 ].…”

Section: Discussionsupporting

confidence: 89%

“…The role of immunity in tumorigenesis has been widely identified [ 58 – 60 ]. It has been reported that CTHRC1 can regulate immune cells to mediate the development and progression of cancers, including colorectal [ 16 ], ovarian [ 61 ], endometrial [ 62 ]and pancreatic cancer [ 63 ]. In this study, our results further imply that CTHRC1 is associated with immune cell infiltration in various cancers (Fig.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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Background The function of collagen triple helix repeat containing 1 (CTHRC1) as an oncogene has been reported in a growing number of publications. Bioinformatics methods represent a beneficial approach to examine the mechanism and function of the CTHRC1 gene in the disease process of cancers from a pan-cancer perspective. Methods In this study, using the online databases UCSC, NCBI, HPA, TIMER2, Oncomine, GEPIA, UALCAN, cBioPortal, COSMIC, MEXPRESS, STRING, CCLE, LinkedOmics, GTEx, TCGA, CGGA, and SangerBox, we focused on the relationship between CTHRC1 and tumorigenesis, progression, methylation, immunity, and prognosis. qPCR was used to detect CTHRC1 expression in glioma tissues and cell lines. Results The pan-cancer analysis showed that CTHRC1 was overexpressed in most tumors, and a significant correlation was observed between CTHRC1 expression and the prognosis of patients with cancer. CTHRC1 genetic alterations occur in diverse tumors and are associated with tumor progression. Levels of CTHRC1 promoter methylation were decreased in most cancer tissues compared with normal tissues. In addition, CTHRC1 coordinated the activity of ICP genes through diverse signal transduction pathways, was also associated with immune cell infiltration and the tumor microenvironment, and potentially represented a promising immunotherapy target. We identified CTHRC1-related genes across cancers using the GEPIA2 tool. The single-gene GO analysis of CTHRC1 across cancers showed that it was involved in some signaling pathways and biological processes, such as the Wnt signaling pathway, cell migration, and positive regulation of protein binding. The expression and function of CTHRC1 were also further verified in glioma tissues and cell lines. Conclusions CTHRC1 is overexpressed in various cancer types and functions as an important oncogene that may promote tumorigenesis and development through different mechanisms. CTHRC1 may represent an important therapeutic target for human cancers.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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“…The gene FOLH1 (folate hydrolase 1) is of particular interest since it codes for the transmembrane metalloenzyme PSMA (prostate-specific membrane antigen). PSMA is the target for an FDA-approved 68 Ga-based peptidomimetic radiotracer for PET imaging of PrCa [117]. Although FOLH1 is not included in Table 1 or Table S2, the gene's transcriptional upregulation is significant for both PrCa primary tumors (fold change and SNR relative to normal prostate are 1.42 and 0.20, respectively), and PrCa metastasis (fold change and SNR relative to primary tumors are 1.89 and 0.30, respectively).…”

Section: Discussionmentioning

confidence: 99%

“…Several PrCa metastasis-upregulated proteins predicted to be part of the secretome have been proved experimentally as potential markers for ELISA assays. These include the proteins APLN (apelin) [64,67], ANGPT2 (angiopoietin 2) [66], CTHRC1 (collagen triple helix repeat containing 1) [68], ESM1(endothelial cell-specific molecule 1) [69], ADAM12 (ADAM metallopeptidase domain 12) [70], PDGFB (platelet-derived growth factor subunit B) [71], and STC2 (stanniocalcin 2) [72,73]. It will not be surprising if more proteins listed in Table 2 may also prove good candidates for serum-or even urine-based tests for PrCa metastasis detection and monitoring.…”

Section: Discussionmentioning

confidence: 99%

“…An elevated level of APLN in serum correlated with esophageal squamous cell carcinoma metastasis [67]. Other secreted protein markers, listed in Table 2, that have been demonstrated as indicators of cancer are CTHRC1 (metastatic colon cancer) [68], ESM1 (metastatic colon cancer) [69], ADAM12 (advanced stage prostate cancer) [70], PDGFB (oral squamous cell carcinoma) [71], and STC2 (laryngeal squamous cell carcinoma) [72,73].…”

Section: Among the Metastasis-specific Upregulated Genes Are Those Coding For Cell Surface-bound Proteinsmentioning

confidence: 99%

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A Unified Transcriptional, Pharmacogenomic, and Gene Dependency Approach to Decipher the Biology, Diagnostic Markers, and Therapeutic Targets Associated with Prostate Cancer Metastasis

Bacolod

Barany

2021

Cancers

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This manuscript demonstrates how integrated bioinformatic and statistical reanalysis of publicly available genomic datasets can be utilized to identify molecular pathways and biomarkers that may be clinically relevant to metastatic prostate cancer (mPrCa) progression. The most notable observation is that the transition from primary prostate cancer to mPrCa is characterized by upregulation of processes associated with DNA replication, metastasis, and events regulated by the serine/threonine kinase PLK1. Moreover, our analysis also identified over-expressed genes that may be exploited for potential targeted therapeutics and minimally invasive diagnostics and monitoring of mPrCa. The primary data analyzed were two transcriptional datasets for tissues derived from normal prostate, primary prostate cancer, and mPrCa. Also incorporated in the analysis were the transcriptional, gene dependency, and drug response data for hundreds of cell lines, including those derived from prostate cancer tissues.

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The impact of SOX4‐activated CTHRC1 transcriptional activity regulating DNA damage repair on cisplatin resistance in lung adenocarcinoma

Ai,

Huang,

Rong

et al. 2024

Electrophoresis

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Lung adenocarcinoma (LUAD) is the predominant subtype within the spectrum of lung malignancies. CTHRC1 has a pro‐oncogenic role in various cancers. Here, we observed the upregulation of CTHRC1 in LUAD, but its role in cisplatin resistance in LUAD remains unclear. Bioinformatics analysis was employed to detect CTHRC1 and SRY‐related HMG‐box 4 (SOX4) expression in LUAD. Gene Set Enrichment Analysis predicted the enriched pathways related to CTHRC1. JASPAR and MotifMap databases predicted upstream transcription factors of CTHRC1. Pearson analysis was conducted to analyze the correlation between genes of interest. The interaction and binding relationship between CTHRC1 and SOX4 were validated through dual‐luciferase and chromatin immunoprecipitation assays. Quantitative real‐time polymerase chain reaction determined the expression of CTHRC1 and SOX4 genes. CCK‐8 was performed to assess cell viability and calculate IC50 value. Flow cytometry examined the cell cycle. Comet assay and western blot assessed DNA damage. CTHRC1 and SOX4 were upregulated in LUAD. CTHRC1 exhibited higher expression in cisplatin‐resistant A549 cells compared to cisplatin‐sensitive A549 cells. Knockdown of CTHRC1 enhanced DNA damage during cisplatin treatment and increased the sensitivity of LUAD cells to cisplatin. Additionally, SOX4 modulated DNA damage repair (DDR) by activating CTHRC1 transcriptional activity, promoting cisplatin resistance in LUAD cells. SOX4 regulated DDR by activating CTHRC1, thereby enhancing cisplatin resistance in LUAD cells. The finding provides a novel approach to address clinical cisplatin resistance in LUAD, with CTHRC1 possibly serving as a candidate for targeted therapies in addressing cisplatin resistance within LUAD.

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CTHRC1 promotes liver metastasis by reshaping infiltrated macrophages through physical interactions with TGF-β receptors in colorectal cancer

Cited by 49 publications

References 54 publications

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

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

A Unified Transcriptional, Pharmacogenomic, and Gene Dependency Approach to Decipher the Biology, Diagnostic Markers, and Therapeutic Targets Associated with Prostate Cancer Metastasis

The impact of SOX4‐activated CTHRC1 transcriptional activity regulating DNA damage repair on cisplatin resistance in lung adenocarcinoma

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