Abstract
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.
Highlights
Colorectal cancer (CRC) is the third most common diagnosed cancer and the fourth leading cause of cancer-related mortality worldwide
Since SW480 and SW620 cells were isolated from the same patient, they were selected as the “host” cell to evaluate the functional properties of HPSE in colorectal cancer cells
High expression of HPSE has been reported in colorectal cancer (CRC) and is correlated with poor prognosis and liver metastasis [10, 15]
Summary
Colorectal cancer (CRC) is the third most common diagnosed cancer and the fourth leading cause of cancer-related mortality worldwide. Tumor invasion and metastasis are the main causes of mortality in CRC patients [1, 2]. The upregulation of HPSE has been implicated in many types of cancers, including CRC [7, 10,11,12,13]. Both HPSE mRNA and protein are practically undetectable in morphologically normal colon epithelium, but are induced during colon carcinogenesis [14,15,16]. The clinical significance of HPSE is well documented, the mechanisms of HPSE-mediated CRC invasion and metastasis need to be further explored
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