Cathepsin L promotes angiogenesis by regulating the CDP/Cux/VEGF-D pathway in human gastric cancer
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ORIGINAL ARTICLE
Cathepsin L promotes angiogenesis by regulating the CDP/Cux/ VEGF‑D pathway in human gastric cancer Tao Pan1 · Zhijian Jin1 · Zhenjia Yu1 · Xiongyan Wu1 · Xinyu Chang1 · Zhiyuan Fan1 · Fangyuan Li1 · Xiaofeng Wang2 · Zhen Li1 · Quan Zhou1 · Jianfang Li1 · Bingya Liu1 · Liping Su1 Received: 7 February 2020 / Accepted: 24 April 2020 © The Author(s) 2020
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. Keywords CTSL · Cux · VEGF-D · Angiogenesis
Tao Pan, Zhijian Jin and Zhenjia Yu contributed equally to this article. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10120-020-01080-6) contains supplementary material, which is available to authorized users.
Abbreviations CTSL Cathepsin L GC Gastric cancer VEGF-D Vascular endothelial growth factors D CDP/Cux1 CCAAT displacement protein/cut like homeobox 1 FBS Fetal bovine serum
* Bingya Liu [email protected]
Background
* Liping Su [email protected]
Gastric cancer (GC) is one of the most common and deadliest types of cancer worldwide, with particularly high morbidity and mortality in China [3, 7]. Nearly, half of all patients with GC develop metastases. At present, surgery is the major curative treatment for GC; however, the prognosis of GC remains poor [2, 35]. Therefore, the exploration of new GC treatment strategies is needed.
1
Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin H
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