Table_4_Heparanase Promotes Tumor Growth and Liver Metastasis of Colorectal Cancer Cells by Activating the p38/MMP1 Axis.xlsx

Heparanase (HPSE), the only known mammalian endoglycosidase responsible for heparan sulfate cleavage, is a multi-faceted protein affecting multiple malignant behaviors in cancer cells. In this study, we examined the expression of HPSE in different colorectal cancer (CRC) cell lines. Gene manipulation was applied to reveal the effect of HPSE on proliferation, invasion, and metastasis of CRC. Knockdown of HPSE resulted in decreased cell proliferation in vitro, whereas overexpression of HPSE resulted in the opposite phenomenon. Consistently, in vivo data showed that knockdown of HPSE suppressed tumor growth of CRC. Furthermore, knockdown of HPSE inhibited invasion and liver metastasis in vitro and in vivo. RNA-sequencing analysis was performed upon knockdown of HPSE, and several pathways were identified that are closely associated with invasion and metastasis. In addition, HPSE is positively correlated with MMP1 expression in CRC, and HPSE regulates MMP1 expression via p38 MAPK signaling pathway. In conclusion, our data demonstrate that HPSE knockdown attenuated tumor growth and liver metastasis in CRC, implying that HPSE might serve as a potential therapeutic target in the treatment of CRC.

肝素酶（HPSE），作为唯一已知的哺乳动物内糖苷酶，负责降解肝素硫酸酯，是一种多功能的蛋白，能够影响癌细胞的多重恶性表型。在本研究中，我们探究了不同结直肠癌（CRC）细胞系中HPSE的表达情况。通过基因操作技术，揭示了HPSE对CRC细胞增殖、侵袭和转移的影响。HPSE的敲低在体外实验中导致细胞增殖减少，而其过表达则产生相反效应。体内实验数据亦显示，HPSE的敲低能够抑制CRC肿瘤的生长。此外，HPSE的敲低在体外和体内实验中均抑制了肿瘤的侵袭和肝转移。在HPSE敲低后，进行了RNA测序分析，识别出与侵袭和转移密切相关的多个通路。此外，HPSE与CRC中MMP1的表达呈正相关，且通过p38 MAPK信号通路调控MMP1的表达。综上所述，我们的数据显示，HPSE敲低可减轻CRC肿瘤的生长和肝转移，暗示HPSE可能成为CRC治疗中的潜在治疗靶点。