Overexpression of sulfatase-1 in murine hepatocarcinoma Hca-F cell line downregulates mesothelin and leads to reduction in lymphatic metastasis, bothin vitroandin vivo

Abstract

Lymphatic vessels function as transport channels for tumor cells to metastasize from the primary site into the lymph nodes. In this experiment we evaluated the effect of Sulfatase-1 (Sulf-1) on metastasis by upregulating it in murine hepatocarcinoma cell line Hca-F with high lymph node metastatic rate of >75%. The study in vitro showed that upregulation of Sulf-1 in Hca-F cells significantly reduced cell proliferation, migration and invasion (p<0.05). Also, the forced expression of Sulf-1 downregulated Mesothelin (Msln) at both the protein and mRNA levels. The experiment in vivo further showed that up-regulation of Sulf-1 with the attendant downregulation of mesothelin delayed tumor growth and decreased lymph node metastasis. In conclusion, our findings show that Sulf-1 is an important tumor suppressor gene in hepatocellular carcinoma (HCC), and its overexpression downregulates Msln and results in a decrease in HCC cell proliferation, migration, invasion, and lymphatic metastasis. This functional relationship between Sulf-1 and Msln could be exploited for the development of a novel liver cancer therapy.

Sulfatase-1 knockdown promotes in vitro and in vivo aggressive behavior of murine hepatocarcinoma Hca-P cells through up-regulation of mesothelin

“…Sulf‐1 has been reported to inhibit the factors which are associated with tumorigenesis and lymphagiogenesis in virous cancers (Lai et al 2008). Consistent with our previous study (Mahmoud et al 2016) both the in vitro and in vivo investigations of the index study strongly suggest a tumor suppressor effect for Sulf‐1 in murine hepatocarcinoma and its expression inhibits Msln expression and reduces LNM rates.…”

“…In agreement with our previous work which showed that up-regulation of Sulf-1 inhibited cell proliferation of Hca-F cells (Mahmoud et al 2016), our current work indicated that, down regulation of Sulf-1 significantly promotes the cell proliferation of Hca-P cells in vitro. Compared to the Hca-P and shRNA-Nc-Hca-P cells, shRNA-Sulf-1-Hca-P cells exhibited enhanced cell proliferation seen on 3rd and 4th days with a statistical significance of P < 0.05 ( Fig.…”

“…Recently, in our previously study we found that Sulf-1 was linked to the lymphatic metastasis of hepatocarcinoma (Mahmoud et al 2016). Using murine hepatocarcinoma Hca-P cell line, we found that down regulation of Sulf-1 in Hca-P cell line promoted cell proliferation, migration and invasion in vitro, and promoted tumor growth and metastasis in vivo.…”

“…It our previous study we have shown that, expression of Sulf‐1 in HCC led to induction of G0‐G1 and G2‐M phase arrest through inhibition of Msln (Mahmoud et al 2016), and Msln is a known tumor promoter gene and its expression is reported to speed G1‐S phase transition in the cell cycle (Tang et al 2013). In our current study, we have shown that down regulation of Sulf‐1 significantly speeds up cell cycle transition through the G1 to S‐phase and then to G2‐M phase.…”

“…The two cell lines have unique features for the study of lymphatic metastasis (Cui et al 2006;Song et al 2005;Hou et al 2001;Li et al 1998). Our previous work indicated that there is a functional relationship between Sulf-1 and Msln in murine hepatocarcinoma (Mahmoud et al 2016). Its overexpression in Hca-F murine hepatocarcinoma cell line down regulates Msln and leads to suppression of the in vitro proliferation, migration and invasion, as well as in vivo tumor growth and LNM rate.…”