Abstract
BackgroundIncreasing 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.MethodsThe 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.ResultsIn 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.ConclusionThe 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.
Highlights
Increasing evidence indicates that angiogenesis plays an important role in tumor progression
To further evaluate the function of nuclear cathepsin L (CTSL) in gastric cancer (GC), we analyzed the expression level of the nuclear fractions of CTSL in GC, and the results showed that the average expression score for the nuclear fractions of CTSL was significantly higher in GC tissues than that in adjacent nontumor tissues (Fig. 1d)
We further identified that prognosis of cases with high nuclear CTSL expression was worse (Fig. 1g) and multivariate analyses of different prognostic parameters revealed that nuclear CTSL expression was an independent factor for overall survival (p = 0.026) (Fig. 1h)
Summary
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. 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. Cathepsins, containing about 15 classes in human, are defined as protease enzymes with versatile functions [24]. These enzymes are vital for normal physiological processes, such as innate immunity, apoptosis, autophagy, and angiogenesis [4]. Our study showed that CTSL is found in the nucleus of GC; overexpression of nuclear CTSL in tumor tissues was significantly associated with differentiation, local invasion, TNM stage, lymph metastasis, and shorter survival of GC patients. Loss- and gainof-function assays demonstrated that CTSL promotes tumor angiogenesis in GC
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