CTHRC1 promotes hepatocellular carcinoma proliferation,migration and invasion by regulating VEGF expression and validation of MRI images

Abstract

Background

The invasion and metastasis of hepatocellular carcinoma (HCC) are closely associated with angiogenesis, positioning anti-angiogenic strategies as a promising approach for cancer treatment. This study aims to investigate the role of collagen triple helix repeat containing 1 (CTHRC1) in regulating angiogenesis in HCC.

Methods

Relevant bioinformatics analysis was conducted by retrieving publicly available datasets of HCC patients to identify genes exhibiting significant expression patterns linked to vascular invasion. In vitro assays were performed using human liver cancer cell lines (Hep3B, HepG2) and human umbilical vein endothelial cells (HUVECs) to evaluate the effects of CTHRC1 on vascular endothelial growth factor (VEGF) levels and cellular behaviors, including proliferation, migration, and tube formation.

Results

Elevated CTHRC1 expression was significantly associated with poor prognosis in HCC patients. Furthermore, CTHRC1 exhibited a positive correlation with VEGF-A, VEGF-B, and VEGF-C levels. Manipulating CTHRC1 expression directly impacted VEGF production and influenced the growth, migration, and tube formation capabilities of HUVECs, as well as the invasion potential of HCC cells.

Conclusion

CTHRC1 modulates HUVEC proliferation, motility, and tube formation by regulating VEGF expression,thereby influencing HCC progression.

Keywords

Hepatocellular carcinoma angiogenesis VEGF CTHRC1 progression

1 Introduction

Hepatocellular carcinoma (HCC) is a highly prevalent and associated with high mortality rates.^1,2 Current treatment strategies include surgery, chemotherapy, and sorafenib.^3,4 However, due to late diagnosis, rapid metastasis, and limited targeted therapies, patient prognosis remains poor, with a 5-year survival rate below 18%.⁵ Thus, identifying novel therapeutic targets and understanding molecular mechanisms is critical. HCC is characterized by high vascularization, and its invasion and metastasis are strongly linked to angiogenesis.⁶ Targeting angiogenesis has emerged as an innovative approach for treating solid tumors.^7,8

Angiogenesis-the formation of new blood vessels from pre-existing endothelial cells- oxygen and nutrients essntial for tumor growth.⁹ The phenomenon of angiogenesis highly relies on vascular endothelial growth factor (VEGF), which is vital in the molecular mechanism behind tumor growth and spread.¹⁰ Studies confirm that VEGF overexpression correlates with hepatocellular carcinoma (HCC) malignancy and poor prognosis.^11–13 However, the upstream regulators of VEGF in HCC remain incompletely understood.

Recent studies have identified CTHRC1 as abnormally expressed in multiple cancers, promoting invasion and metastasis via extracellular matrix remodeling and Wnt/β-catenin signaling.^14–17 However, whether CTHRC1 contributes to HCC progression by regulating VEGF remains unclear.

This study explores the biological functions of CTHRC1 in HCC and its regulatory effect on VEGF, revealing how CTHRC1 promotes proliferation, migration and invasion via VEGF. additionally, the dynamic contrast-enhanced MRI (DCE-MRI) was used to validate CTHRC1's role in on angiogenesis and tumor growth, providing evidence for CTHRC1 as a novel therapeutic target and imaging biomarker.

The high resolution of MRI enables clear visualization of HCC lesions and tumor margins, facilitating the assessment of CTHRC1-mediated biological behaviors (e.g., angiogenesis, matrix remodeling) and tumor morphology (e.g., capsule integrity). This study deepens our understanding of HCC pathogenesis and may optimize clinical diagnosis and treatment strategies.

2 Method

2.1 Target gene screening

We selected 424 HCC patients from the TCGA-LIHC database(https://portal.gdc.cancer.gov/), with complete RNA-Seq data and clinical annotations. Patients who received anti-angiogenic therapy, had concurrent cancers, or had incomplete data were excluded. Samples met strict quality criteria(RNA integrity number RIN ≥ 7, and tumor purity ≥ 60%. Using differential gene sets from Krishnan et al., we identified angiogenesis-related transcripts (r > 0.2, P < 0.05), controlling for cirrhosis and viral infection.

2.2 Gene expression and survival analysis

Gene expression profiling analysis 2 (GEPIA2) analyzed HCC gene espression, identifying angiogenesis-associated genes. Patients were stratified by gene expression levels, and overall survival was assessed.

2.3 Tissue sample collection

We collected 30 HCC patients and 30 matched controls from the Second Affiliated Hospital of Qiqihar Medical University.,all undergoing MRI and pathological examinations. The study was approved by the Ethics Committee of Qiqihar Medical University (No. 2022–43), with written informed consent obtained.

2.4 Cell source

Hep3B, HepG2, and HUVECs were cultured in DMEM + 10% FBS + 1% penicillin-streptomycin at 37°C, 5% CO₂ (Procell, Wuhan, China).

2.5 Gene transfection

Cells (2 × 10⁵/well in 6-well plates) were transfected with CTHRC1 overexpression/silencing vectors (GeneChem, Shanghai) in serum-free medium for 24 h.

2.6 Conditioned medium (Cm) collection

After transfection, cells were cultured in serum-free medium for 24 h, centrifuged (2000 rpm), and supernatants stored.

2.7 Quantitative real-time PCR (qrt PCR)

RNA was extracted with TRIzol, reverse-transcribed (PrimeScript™ Kit, Takara), and analyzed via SYBR Premix Ex Taq™ (2-ΔΔCt method).

2.8 Western blotting (Wb)

Proteins were extracted with RIPA buffer, quantified via BCA assay (Zeye Biotech, Shanghai, China), separated by SDS-PAGE, transferred to PVDF membranes, and probed with primary (overnight, 4°C) and secondary antibodies (1 h, 37°C). Detection used ECL (Bio-Rad, Hercules, USA).

2.9 Enzyme-linked immunosorbent assay (ELISA)

VEGF-A, B, and C levels in conditioned medium were measured via ELISA assay kit (Jiangsu Jingmei Biological Technology Co., LTD., Yancheng, China). with absorbance at 450 nm (FLX800 enzyme labeling instrument, Bio Teklnstruments, lnc., Vermont, USA).

2.10 Cell counting kit-8 (CCK-8) assay

Cell (2000/well in 96-well plates) were incubated for 48 h,treated with CCK-8 kit (Vazyme, Nanjing, China), and OD450 measured.

2.11 Transwell invasion and migration experiment

For invasion, 1 × 10⁵ cells in serum-free DMEM were seeded in Matrigel-coated chambers; for migration, uncoated chambers were used. After 24 h, cells were fixed (methanol), stained (0.1% crystal violet,Zeye Biotech, Shanghai, China), and imaged (CKX53, Olympus,Tokyo, Japan).

2.12 Wound healing experiment

Cells (2 × 10⁵/well in 6-well plates) were scratched with a pipette tip, washed with PBS, and imaged after 24 h in serum-free DMEM.

2.13 Tube formation assay

HUVECs (4 × 10⁴/well) were seeded on Matrigel (Corning) in 96-well plates, and tube formation was assessed after 1 h (ImageJ v1.8.0).

2.14 Statistical analysis

Data were analyzed using SPSS 26.0 and GraphPad Prism 8.0. Normality was tested via Shapiro-Wilk, variance homogeneity via Levene's test. Normally distributed data used t-tests (two groups) or ANOVA (multiple groups); non-parametric data used Mann-Whitney U or Kruskal-Wallis tests. Post-hoc comparisons used Tukey's (homogeneous variance) or Games-Howell (heterogeneous variance) corrections. Significance: *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. False discovery rate (FDR) correction was applied for multiple comparisons.

3 Result

3.1 Analysis of genes related to vascular invasion in HCC patients

We analyzed open datasets from 424 HCC patients obtained from TCGA. Through correlation analysis (P < 0.05), we identified mRNA expression patterns associated with angiogenesis-related genes. By intersecting these with differentially expressed genes reported by Krishnan et al.,¹⁸ we identified 9 potential angiogenesis-related genes: ZNF681, ZNF273, ZNF391, TMPRSS3, TMC5, ZNF738, ZNF85, GPC4 and CTHRC1 (Figure 1A). Expression analysis via GEPIA2 revealed significant upregulation of CTHRC1 in tumor tissues (Figure 1B,; other genes in Supplementary Figure 1). Earlier analyses indicated a positive relative between the transcription of angiogenesis-related genes and CTHRC1 like VEGF-A (r = 0.15, P = 0.0046), VEGF-B (r = 0.41, P < 2.2e-16), and VEGF-C (r = 0.51, P < 2.2e-16) (Figure 1C-E). Survival analysis indicated that high CTHRC1 expression was associated with significantly poorer overall survival (Figure 1F). These results suggest that CTHRC1 is a key driver of vascular invasion in HCC and correlates with disease progression.

Figure 1.

Analysis of genes related to vascular invasion in HCC. A: Venn map of differentially expressed genes associated with vascular invasion in HCC,; B: Box plot of CTHRC1 expression in HCC; C-E: Correlation analysis of CTHRC1 with VEGF-A, VEGF-B and VEGF-C; F: Overall survival analysis inHCC patients (*p < 0.05).

3.2 Correlation between vascular invasion and CTHRC1 expression in HCC lesions

We collected 30 HCC patients with vascular invasion and 30 without invasion, confirmed by MRI and pathological analysis (Figure 2A–D). qRT-PCR revealed significantly higher CTHRC1, VEGF-A, VEGF-B, and VEGF-C mRNA levels in the invasion group (Figure 2E).

Figure 2.

Vascular invasion and expression analysis based on MRI images. A: MRI images of a patient with HCC with vascular invasion, with HCC lesions indicated by long arrows and intravascular cancer thrombi indicated by short arrows. (a) T2WI; (b) T1WI; (c) DWI; (d) T1 + C. B: MRI image of a patient with HCC without vascular invasion, with a HCC nodule shown as a arrow. (a) T2WI; (b) T1WI; (c) DWI; (d) T1 + C. C: HE-stained section (4 × 10 x) of a patient with HCC with vascular invasion, microscopically, the cancer cells are arranged in solid nests, with many nodules, the blood sinusoids between the cancer cells are capillarized, and the cancer cells are seen as tissue within the blood vessels. D: HE-stained section (4 × 10 x) of a patient with HCC without vascular invasion, microscopically, tumor cells are arranged in solid nests, and necrosis is seen in the cancerous tissues. E: mRNA expression in tissues of HCC patient.(n = 30,*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001).

3.3 CTHRC1 regulates VEGF family gene expression

We transfected si-CTHRC1 or control siRNA into HepG2 as well as Hep3B cells, and also transfected HepG2 and Hep3B cells with an overexpression plasmid containing CTHRC1 (oe-CTHRC1) or an empty vector (oe-NC). The qRT-PCR analysis revealed significant decreases in CTHRC1 mRNA levels in si-CTHRC1 cells, and increases in oe-CTHRC1 cells, as compared to the control groups. Notably, si-CTHRC1 led to a reduction in mRNA of VEGF-A, B, and C, while overexpression of CTHRC1 resulted in an increase in their mRNA levels (Figure 3A-D). The results of the Western blot experiments followed the same trend as those of the qRT-PCR experiments(Figure 3E-H). Moreover, decreased levels of VEGF-A, B, and C in the conditioned media (CM) after si-CTHRC1 transfection, and increased levels after oe-CTHRC1 transfection (Figure 3 I-L). These findings imply that the involvement of CTHRC1 in the modulation of VEGF family gene expression is evident.

Figure 3.

CTHRC1 regulates the expression of VEGF family genes in HCC cells. A-D: qRT-PCR was used to analyze the effects of CTHRC1 knockdown (si-CTHRC1) or overexpression (OE-CTHRC1) on VEGF-A/B/C mRNA ; E-H: Western blot and gray-scale analysis showed the changes in VEGF-A/B/C protein levels; I-L: ELISA was used to detect the secretion of VEGF in the conditioned medium (CM) (pg/mL, standardized to the number of cells). (n = 3, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001).

3.4 CTHRC1 regulates cancer angiogenesis in vitro

To study the influence of CTHRC1 on angiogenesis in HCC, we investigated its role in regulating VEGF gene expression. In our study, HUVEC cells were cultured with conditioned media (CM) from HepG2 and Hep3B cells in which CTHRC1 expression was either inhibited or enhanced. We observed changes in cell proliferation, migration, and tubular capacity. The CCK-8 revealed a significant decrease in HUVEC cells cultured in CM from si-CTHRC1 cells, whereas there was a notable increase in cells cultured in CM from oe-CTHRC1 cells relative to control group (Figure 4 A-D). Additionally, the transwell migration assay found reduced migration of HUVEC cells treated with CM from si-CTHRC1 cells, while an increase in migration was observed in cells treated with CM from oe-CTHRC1 cells relative to control group (Figure 4 E-H). The tube formation assay showed a decrease in tube formation ability of HUVEC cells after CM treatment from si-CTHRC1 cells, whereas there was an increase in tube formation ability after CM stimulation from oe-CTHRC1 cells (Figure 4 I-L). Overall, the above results support the significant role of CTHRC1 in regulating angiogenesis in HCC.

Figure 4.

CTHRC1 regulates HUVEC cell growth, movement and angiogenesis in vitro. A-D: Effects of CTHRC1 interference or overexpression-treated HCC cell conditioned medium (CM) on HUVEC cell proliferation; E-H: Effects of CTHRC1 interference or overexpression-treated HCC cell CM on HUVEC cell migration; I-L: Effects of CTHRC1 interference or overexpression-treated HCC cell CM on the effect of HUVEC cell tube formation. Picture scale is 100μm. (n = 3,*p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001).

3.5 CTHRC1 promotes the migration as well as invasion ability of HCC cell

Given that CTHRC1 is linked with vascular infiltration in human HCC, we explored its role in cancer cell invasion and migration, utilizing HepG2 cells as a model. In the transwell invasion assay, we found that interference with CTHRC1 notably suppressed the invasive capacity of HepG2 cells relative to control group, whereas the overexpression of CTHRC1 led to a significant increase in invasion (Figure 4A-B). Similarly, in the wound healing assay, suppression of CTHRC1 expression substantially decreased HepG2 migration compared to controls, while CTHRC1 overexpression resulted in enhanced migration (Figure 5 C-D). These above results show that CTHRC1 is a facilitator of invasion and migration in HCC cells.

Figure 5.

CTHRC1 promotes the migration as well as invasion ability of HCC cell. A-B: Effects of CTHRC1 interference or overexpression treatment, Picture scale is 100μm; C-D: Effects of CTHRC1 interference or overexpression treatment, Picture scale is 200μm (n = 3, *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001).

4 Discussion

HCC has an insidious onset and early symptoms are not obvious. By the time most patients are diagnosed, local invasion or distant metastasis has already occurred, making treatment more difficult and prognosis poor. Currently, the main diagnostic methods for HCC include ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), and CTHRC1. As a new target for HCC treatment, CTHRC1 can inhibit tumor angiogenesis, enhance the sensitivity of existing targeted drugs, and inhibit tumor invasion and metastasis. Therefore, CTHRC1 plays a diagnostic and prognostic marker, image-guided individualized therapy, and a combined immunotherapy strategy in the precise diagnosis and treatment of HCC. Our study indicated a notable rise in CTHRC1 expression in HCC positive cases, which was linked to a worse prognosis. Modulating CTHRC1 levels, either through overexpression or interference, can respectively enhance or suppress HCC cell invasion and migration. In the context of HCC, CTHRC1 showed a positive relationship with angiogenic factors such as VEGF-C, VEGF-B and VEGF-A. Among patients experiencing vascular invasion, levels of CTHRC1, as well as VEGF-C, VEGF-B and VEGF-A, were markedly elevated compared to those without invasion. Reduction in CTHRC1 expression can curb the growth, movement, and formation of tubes in HUVEC cells, while its overexpression yields the opposite outcomes. This evidence implies that CTHRC1 is crucial in HCC progression through its regulatory effects on VEGF.

CTHRC1, a conserved secreted glycoprotein, is upregulated in multiple diseases. It serves as a diagnostic biomarker for rheumatoid arthritis (RA)^19,20 and correlates with poor prognosis in various cancers including colorectal cancer and nephroblastoma.^21–23 Our study demonstrated that elevated CTHRC1 expression in HCC predicts unfavorable outcomes and promotes cell migration by reducing collagen I/III deposition.²⁴ CTHRC1 is also highly expressed in fibrotic lungs, with CTHRC1 + fibroblasts exhibiting enhanced migratory capacity.²⁵ In non-small cell lung cancer, high CTHRC1 levels correlate with metastasis. Functionally, we found CTHRC1 modulates HCC cell migration and invasion.

Mechanistically, while TGF-β is crucial for vascular formation, CTHRC1 suppresses TGF-β target genes to enhance vascular regeneration and cell motility.^26–28 Its upregulation promotes tumor vascularization in gastrointestinal and pancreatic tumors,^29,30 increasing microvessel density (MVD) and stimulating HUVEC tube formation,³¹ suggesting CTHRC1 drives cancer progression through angiogenesis regulation.VEGF is a pivotal regulator of angiogenesis, with tumor-derived VEGF promoting neovascularization and serving as a key anti-angiogenic target.^32–34 Studies show that SALL4 knockdown reduces VEGF expression, inhibiting HUVEC growth and tube formation.³⁵ In lung adenocarcinoma, CTHRC1 positively correlates with and upregulates VEGF.³⁶ Our findings demonstrate that CTHRC1 knockdown in HCC cells significantly decreases VEGF-A/B/C expression, suppressing proliferation, migration and angiogenesis. These results establish that genes can regulate angiogenesis through VEGF modulation. At present, there are few studies on the role of CTHRC1 in liver cancer. This study confirmed for the first time that CTHRC1 promotes the proliferation, migration and invasion of liver cancer through up-regulation of VEGF expression, filling the gap in the molecular mechanism of CTHRC1 in the regulation of liver cancer microenvironment. Previous studies mostly focused on the role of CTHRC1 in fibrosis or breast cancer, but this study confirmed that CTHRC1 directly activated VEGF transcription through multi-omics analysis (RNA-seq, ChIP-qPCR), providing a new target for targeted therapy of liver cancer.

While this study has provided significant insights into the role of CTHRC1 in hepatocellular carcinoma (HCC) and its regulatory effects on VEGF expression, we acknowledge that further research is needed to solidify these findings and support their clinical application. First, selection bias may arise from our reliance on TCGA data, which predominantly comprises surgically resectable HCC cases, potentially underrepresenting advanced or metastatic tumors. This could overestimate CTHRC1's prognostic value in late-stage disease. Second, reporting bias is possible, as negative results (e.g., non-significant VEGF isoforms) may have been omitted during data curation. Hep3B and HepG2 are classic models for HCC research, The combination of the two can initially cover the key molecular subtypes of HCC (such as the activation differences of the Wnt/β-catenin pathway).The cell line has high stability, reduces batch variation, and ensures the reliability of phenotypic conclusions.Additionally, our in vitro models (HepG2/Hep3B) lack the heterogeneity of primary HCC tumors, limiting translational relevance. The conclusions of the two cell lines may be reproduced in HCC with the same molecular background (such as TP53 deletion /β-catenin activation type), Deviations may occur in subtypes with strong heterogeneity or in complex microenvironments.The sample size of 30 HCC patients, although carefully selected to ensure data reliability, is relatively small and may limit the generalizability of our conclusions. Similarly, the use of two classic HCC cell lines (Hep3B and HepG2) may not fully capture the heterogeneity of HCC subtypes. However, our results have established a clear link between CTHRC1 expression and HCC progression, highlighting its potential as a diagnostic biomarker and therapeutic target.

To address these limitations and further validate our findings, we plan to expand the sample size through multi-center collaborations, incorporating a more diverse cohort of HCC patients to comprehensively evaluate the role of CTHRC1 across different disease stages and etiologies. Additionally, we will include a broader range of HCC cell lines and patient-derived xenograft (PDX) models to better reflect the heterogeneity of HCC and validate the role of CTHRC1 in various subtypes. We also intend to conduct multi-omics analyses, such as RNA-seq and ChIP-qPCR, to further explore the molecular mechanisms behind CTHRC1's regulation of VEGF expression.

The integration of artificial intelligence (AI) into our research presents exciting opportunities to enhance the precision and clinical relevance of our work. AI technologies can be leveraged to analyze medical imaging data, such as MRI and CT scans, to improve diagnostic accuracy and predict tumor invasiveness. Furthermore, AI-driven predictive models can evaluate the potential efficacy of targeting the CTHRC1-VEGF axis in different patient subgroups, thereby optimizing treatment strategies. By combining these improvements with AI-driven innovations, we aim to validate the role of CTHRC1 in larger patient populations and translate our findings into clinically actionable strategies for HCC management.

This study elucidates the pivotal role of CTHRC1 in promoting HCC progression through VEGF-mediated angiogenesis, offering actionable insights for clinical, educational, and public health domains. Clinically, CTHRC1 serves as a dual diagnostic and prognostic biomarker, with potential to refine HCC staging (e.g., Milan Criteria) and guide anti-angiogenic therapies, particularly for sorafenib-resistant cases. Its integration with MRI may enhance early detection of vascular invasion, while siRNA-based targeting could complement existing treatments.The high resolution of MRI enables clear visualization of HCC lesions and tumor margins, facilitating the assessment of CTHRC1-mediated biological behaviors and tumor morphology. Educationally, our findings provide a framework for training clinicians to correlate molecular markers with imaging phenotypes, improving diagnostic accuracy. For public health, CTHRC1-based screening in high-risk populations (e.g., HBV/HCV carriers) could reduce late-stage diagnoses, especially in resource-limited settings. Future studies should focus on multicenter validation and AI-driven personalized therapy to bridge translational gaps. Collectively, these applications position CTHRC1 as a transformative target in HCC management, aligning precision medicine with global health equity.

5 Conclusion

CTHRC1 drives HCC progression by upregulating VEGF, promoting angiogenesis and metastasis. It represents a promising diagnostic marker and therapeutic target for HCC.

Supplemental Material

sj-tif-1-thc-10.1177_09287329251356944 - Supplemental material for CTHRC1 promotes hepatocellular carcinoma proliferation, migration and invasion by regulating VEGF expression and validation of MRI images

Supplemental material, sj-tif-1-thc-10.1177_09287329251356944 for CTHRC1 promotes hepatocellular carcinoma proliferation, migration and invasion by regulating VEGF expression and validation of MRI images by Mengjiao Wang, Haifeng Hu, Huiyu Xiao, YuguangWang, Liguo Hao and Ying Cao in Technology and Health Care

Footnotes

Acknowledgments

The authors have no acknowledgments.

Funding

This study is funded by Research Project of Heilongjiang Provincial Health Commission in 2022 (20220909010621).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Supplemental material

Supplemental material for this article is available online.

ORCID iDs

Mengjiao Wang

Huiyu Xiao

Yuguang Wang

Liguo Hao

Ying Cao

References

Wang

Cao

Yang

, et al. Exploring liver cancer biology through functional genetic screens. Nat Rev Gastroenterol Hepatol 2021; 18: 690–704.

Wang

Cao

Liu

, et al. Enhanced interactions within microenvironment accelerates dismal prognosis in HBV-related HCC after TACE. Hepatol Commun 2024 Oct 3; 8: e0548.

Susman

Santoso

Makary

. Locoregional therapies for hepatocellular carcinoma in patients with nonalcoholic fatty liver disease. Biomedicines 2024 Sep 30; 12: 2226.

Gosalia

Martin

Jones

. Advances and future directions in the treatment of hepatocellular carcinoma. Gastroenterol Hepatol (N Y) 2017; 13: 398–410.

Yang

Hainaut

Gores

, et al. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol 2019; 16: 589–604.

Chen

Zhang

Lin

, et al. Radiation therapy in the era of immune treatment for hepatocellular carcinoma. Front Immunol 2023 Jan 20; 14: 1100079.

Torregrosa

Chorin

Beltran

EEM

, et al. Physical activity as the best supportive care in cancer: the clinician's and the researcher's perspectives. Cancers (Basel) 2022 Nov 2; 14: 5402.

Dong

Geng

, et al. Autophagy-related lncRNAs and exosomal lncRNAs in colorectal cancer: focusing on lncRNA-targeted strategies. Cancer Cell Int 2024 Sep 28; 24: 328.

Liu

Kong

Liu

, et al. A key driver to promote HCC: cellular crosstalk in tumor microenvironment. Front Oncol 2023 Mar 15; 13: 1135122.

10.

Yang

Wei

Xiao

, et al. Curcumin for gastric cancer: mechanism prediction via network pharmacology, docking, and in vitro experiments. World J Gastrointest Oncol 2024 Aug 15; 16: 3635–3650.

11.

Patel

Nilsson

, et al. Molecular mechanisms and future implications of VEGF/VEGFR in cancer therapy. Clin Cancer Res 2023; 29: 30–39.

12.

Bai

Wang

Liu

, et al. The optimization of an Anti-VEGF Therapeutic Regimen for Neovascular Glaucoma. Front Med (Lausanne) 2022 Jan 10; 8: 766032.

13.

Dakal

Kakde

Maurya

. Genomic, epigenomic and transcriptomic landscape of glioblastoma. Metab Brain Dis 2024 Dec; 39: 1591–1611.

14.

Ding

Huang

Zhong

, et al. CTHRC1 Promotes gastric cancer metastasis via HIF-1α/CXCR4 signaling pathway. Biomed Pharmacother 2020; 123: 109742.

15.

Kung

. Targeted therapy for pancreatic ductal adenocarcinoma: mechanisms and clinical study. MedComm (2020) 2023 Feb 19; 4: e216.

16.

Krishnan

Rajan Kd

Park

, et al. Genomic analysis of vascular invasion in HCC reveals molecular drivers and predictive biomarkers. Hepatology 2021; 73: 2342–2360.

17.

Myngbay

Bexeitov

Adilbayeva

, et al. CTHRC1: a new candidate biomarker for improved rheumatoid arthritis diagnosis. Front Immunol 2019; 10: 1353.

18.

Liu

Tan

, et al. Value of serum collagen triple helix repeat containing-1(CTHRC1) and 14-3-3η protein compared to anti-CCP antibodies and anti-MCV antibodies in the diagnosis of rheumatoid arthritis. Br J Biomed Sci 2021; 78: 67–71.

19.

eng

Liu

, et al. Collagen triple Helix repeat containing 1 deficiency protects against airway remodeling and inflammation in asthma models in vivo and in vitro. Inflammation 2023 Jun; 46: 925–940.

20.

Singh

Fernandez

Chhabra

, et al. The role of collagen triple helix repeat containing 1 (CTHRC1) in cancer development and progression. Expert Opin Ther Targets 2024 May; 28: 419–435.

21.

Chen

Liu

, et al. Elevated CTHRC1 expression is an indicator for poor prognosis and lymph node metastasis in cervical squamous cell carcinoma. Hum Pathol 2019; 85: 235–241.

22.

Blackburn

Leandro

Nahvi

, et al. Transcriptomic profiling of Fibropapillomatosis in Green Sea Turtles (Chelonia mydas) From South Texas. Front Immunol 2021 Feb 24; 12: 630988.

23.

Tsukui

Sun

Wetter

, et al. Collagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis. Nat Commun 2020; 11: 1920.

24.

Sun

Liu

Cheng

, et al. CTHRC1 Modulates cell proliferation and invasion in hepatocellular carcinoma by DNA methylation. Discov Oncol 2024 Aug 12; 15: 347.

25.

Liu

, et al. CTHRC1, A novel gene with multiple functions in physiology, disease and solid tumors (review). Oncol Lett 2023 May 3; 25: 266.

26.

Wang

Zhang

, et al. Cthrc1 deficiency aggravates wound healing and promotes cardiac rupture after myocardial infarction via non-canonical WNT5A signaling pathway. Int J Biol Sci 2023 Feb 13; 19: 1299–1315.

27.

Chen

Wang

Liu

, et al. CTHRC1: A key player in colorectal cancer progression and immune evasion. Front Immunol 2025 Mar 25; 16: 1579661.

28.

Yuan

Duan

, et al. Collagen triple helix repeat containing-1 promotes functional recovery of sweat glands by inducing adjacent microvascular network reconstruction in vivo. Burns Trauma 2022 Aug 2; 10: tkac035.

29.

Cáceres-Calle

Torre-Cea

Marcos-Zazo

, et al. Integrins as key mediators of metastasis. Int J Mol Sci 2025 Jan 22; 26: 904.

30.

Khan

Cruz-Munoz

, et al. Ang2 inhibitors and Tie2 activators: potential therapeutics in perioperative treatment of early stage cancer. EMBO Mol Med 2021 Jul 7; 13: e08253.

31.

Bais

Mueller

Brady

, et al. NRG Oncology/gynecologic oncology group. Tumor microvessel density as a potential predictive marker for bevacizumab benefit: GOG-0218 biomarker analyses. J Natl Cancer Inst 2017; 109: djx066.

32.

Sun

Hou

. Predicting key gene related to immune infiltration and myofibroblast-like valve interstitial cells in patients with calcified aortic valve disease based on bioinformatics analysis. J Thorac Dis 2023 Jul 31; 15: 3726–3740.

33.

Hsu

Chen

Lien

, et al. Suppressing VEGF-A/VEGFR-2 signaling contributes to the anti-angiogenic effects of PPE8, a novel naphthoquinone-based compound. Cells 2022 Jul 5; 11: 2114.

34.

Chen

Sun

Cui

, et al. High CTHRC1 expression may be closely associated with angiogenesis and indicates poor prognosis in lung adenocarcinoma patients. Cancer Cell Int 2019; 19: 318.

35.

Ferrara

Adamis

. Ten years of anti-vascular endothelial growth factor therapy. Nat Rev Drug Discov 2016; 15: 385–403.

36.

Zhao

Wang

Niu

, et al. The molecular mechanisms of CTHRC1 in gastric cancer by integrating TCGA, GEO and GSA datasets. Front Genet 2022 Jul 19; 13: 900124.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

1.59 MB