Cathepsin L promotes angiogenesis by regulating the CDP/Cux/VEGF-D pathway in human gastric cancer.

Abstract

BACKGROUND:

Increasing evidence indicates that angiogenesis plays an important role in tumor progression. The function of cathepsin L (CTSL), an endosomal proteolytic enzyme, in promoting tumor metastasis is well recognized. The mechanisms by which CTSL has promoted the angiogenesis of gastric cancer (GC), however, remains unclear.

METHODS:

The nuclear expression levels of CTSL were assessed in GC samples. The effects of CTSL on GC angiogenesis were determined by endothelial tube formation analysis, HUVEC migration assay, and chick embryo chorioallantoic membrane (CAM) assay. The involvement of the CDP/Cux/VEGF-D pathway was analyzed by angiogenesis antibody array, Western blot, co-immunoprecipitation (Co-IP) and dual-luciferase reporter assay.

RESULTS:

In this study, we found that the nuclear CTSL expression level in GC was significantly higher than that in adjacent nontumor gastric tissues and was a potential important clinical prognostic factor. Loss- and gain-of-function assays indicated that CTSL promotes the tubular formation and migration of HUVEC cells in vitro. The CAM assay also showed that CTSL promotes angiogenesis of GC in vivo. Mechanistic analysis demonstrated that CTSL can proteolytically process CDP/Cux and produce the physiologically relevant p110 isoform, which stably binds to VEGF-D and promotes the transcription of VEGF-D, thus contributing to the angiogenesis of GC.

CONCLUSION:

The findings of the present study suggested that CTSL plays a constructive role in the regulation of angiogenesis in human GC and could be a potential therapeutic target for GC.

• Authors: Tao Pan, Zhijian Jin, Zhenjia Yu, Xiongyan Wu, Xinyu Chang, Zhiyuan Fan, Fangyuan Li, Xiaofeng Wang, Zhen Li, Quan Zhou, Jianfang Li, Bingya Liu, Liping Su
• Journal: Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association (Gastric Cancer) Vol. 23 Issue 6 Pg. 974-987 (11 2020) ISSN: 1436-3305 [Electronic] Japan
• PMID: 32388635 (Publication Type: Journal Article)

Chemical References

• Angiogenesis Inducing Agents
• CUX1 protein, human
• Homeodomain Proteins
• Repressor Proteins
• Transcription Factors
• Vascular Endothelial Growth Factor D
• Cytidine Diphosphate
• Cathepsin L

Topics

• Angiogenesis Inducing Agents (metabolism)
• Animals
• Cathepsin L (metabolism)
• Chick Embryo
• Cytidine Diphosphate (metabolism)
• Gene Expression Regulation, Neoplastic (genetics)
• Homeodomain Proteins (metabolism)
• Humans
• Repressor Proteins (metabolism)
• Signal Transduction (genetics)
• Stomach Neoplasms (genetics)
• Transcription Factors (metabolism)
• Vascular Endothelial Growth Factor D (metabolism)