Downregulation of SPINK13 Promotes Metastasis by Regulating uPA in Ovarian Cancer Cells

Cai, Shengyun; Zhang, Pei; Dong, Suhe; Li, Li; Cai, Jianming; Xu, Man

doi:10.1159/000487348

Cited by 20 publications

(20 citation statements)

References 39 publications

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“…uPA, a serine protease with multiple function, acts as risk assessment and a possible treatment target in many cancers, [10,17,18] such as breast cancer, [9,19,20] pancreatic cancer, [21,22] prostate cancer, [23,24] and ovarian cancer. [25–27] In particular, uPA can accelerate tumor metastasis and promote tumor angiogenesis by degrading extracellular matrix (ECM) and basement membranes, such as vimentin and fibronectin, involving in epithelial-mesenchymal transition (EMT). [27,28] Moreover, international guidelines (AGO, St. Gallen, ASCO) recommend the use of uPA and plasminogen activator inhibitor-1 (PAI-1) expression to better assess potential clinical benefit from adjuvant systemic treatment of breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Circulating uPA as a potential prognostic biomarker for resectable esophageal squamous cell carcinoma

Xiao

Zhu

et al. 2019

Medicine

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Previous research showed that the 4 genes of matrix metallopeptidase 9 (MMP9), cyto-keratin 20 (CK20), cyto-keratin 19 (CK19) and urokinase type plasminogen activator (uPA) are detectable in the peripheral blood. All the 4 genes are related to tumor invasion and metastasis. However, whether their expression is associated with clinicopathologic factors and the prognosis of patients with esophageal squamous cell carcinoma (ESCC) is still confused. Expression levels of MMP9, CK20, CK19, and uPA were evaluated by quantificational real-time polymerase chain reaction (qRT-PCR) in peripheral blood of 205 ESCC patients who received radical resection. The cut-off value was 1000 copy numbers. Their impacts on clinicopathologic factors and survival were investigated. The uPA expression positively correlated with gender (P = .046) and tumor size (P = .046). Meanwhile, CK19 expression positively correlated with tumor size (P = .029), vascular invasion (P = .024), and CK20 expression positively correlated with tumor size (P = .035) and degrees of differentiation (P = .032). Moreover, the overexpression of MMP9 has a correlation with postoperative radiotherapy (P = .041) and chemotherapy (P = .012). Among the 4 genes, only uPA is a prognostic indicator for disease-free survival and overall survival both in univariate analysis and multivariate analysis (P = .015). This study suggests that circulating uPA mRNA in peripheral blood can serve as a potential unfavorable prognosis biomarker in ESCC. Further perspective, multi-center and large-scale study is still needed.

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Section: Discussionmentioning

confidence: 99%

Circulating uPA as a potential prognostic biomarker for resectable esophageal squamous cell carcinoma

Xiao

Zhu

et al. 2019

Medicine

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“…As a serine protease inhibitor, Hespintor inhibits the direct cleavage and activation of MMP by interacting with uPA, and its expression in non-tumor samples is significantly higher than that in hepatocellular carcinoma samples, especially in advanced hepatocellular carcinoma samples [5]. Except for our group's previous work, it has been reported that Hespintor can promote ovarian cancer metastasis after down-regulated expression of siRNA [10], which shows that Hespintor has strong antitumor activity. Based on the previous studies, the human hepatoma cell line MHCC97-H with high metastatic potential was selected to mimic advanced hepatocarcinoma's highly invasive characteristics [11].…”

Section: Discussionmentioning

confidence: 68%

The Inhibitory Effects of Recombinant Hespintor Combined with Sorafenib on Transplanted Human Hepatoma in Nude Mice, and Transcriptional Regulation of Hespintor Based on RNA-Seq

Lun¹,

Sun²,

Liu³

et al. 2021

J. Cancer

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Objective: As targeted drugs, exogenous serpins could be introduced to patients to restore body balance. This study aimed to observe further the inhibitory effects of recombinant Hespintor (a Kazal-type serpin) combined with Sorafenib on transplanted human hepatoma tumors in nude mice specimens and to explore the possible transcriptional regulation by Hespintor. Methods: A model of human hepatoma tumors transplanted in nude mice was established, and the medication was administrated to observe the growth of the tumors. Four weeks after the drug administration, the tumors were removed to evaluate the inhibition effects of Hespintor on in-situ tumor growth and liver metastasis. The expression levels of MMP2, MMP9, Bax, Bcl-2, and caspase-3 in the tumor organizations were detected with Western blot. The target genes of the Hespintor were screened based on tissue RNA-Seq, and the regulatory network was constructed. Results: It was found that the recombinant Hespintor displayed a significant antitumor effect on the subcutaneous growth of MHCC97-H cells. Moreover, the therapeutic effects of the combination therapy were significantly better than those of single therapy. 10 target genes with significantly different expression by Hespintoron tumor tissue were identified. Finally, a visual regulatory networkwas constructed for target mRNA-pathway. Conclusions: The antitumor effect of Hespintor combined with Sorafenib in treating the subcutaneously implanted hepatocellular carcinoma tumors in nude mice was significant. The possible transcriptional regulation by Hespintor involved multiple signaling pathways, and it was not just the antitumor effect of uPA via its extracellular inhibitions.

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“…Ovarian cancer cells in peritoneal cavity can invade the lined surface and grow above the peritoneal reflection in the pelvis [11]. Although surgery usually involves an en bloc resection of the ovarian tumors, reproductive organs, the sigmoid colon, and a primary bowel reanastomosis, micrometastasis of epithelial ovarian cancer cells via epithelial–mesenchymal–epithelial transition (EMT) did exist and accounted for many recurrence and death cases [12,13]. Therefore, in our study, we examined the role of CHTOP in epithelial ovarian cancer metastasis.…”

Section: Discussionmentioning

confidence: 99%

Chromatin target of protein arginine methyltransferase regulates invasion, chemoresistance, and stemness in epithelial ovarian cancer

Feng

Wang

et al. 2019

Bioscience Reports

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Ovarian cancer is one of the most common gynecological cancers with a high mortality rate in females. Chromatin target of protein arginine methyltransferase (CHTOP) is an important intracellular protein that regulates the transcriptional activation of several oncogenic genes in glioblastomagenesis and controls mature mRNA export as a component of TRanscription-Export complex. However, the role of CHTOP in ovarian cancer is unclear. In the present study, we investigated the correlation between tumor-derived CHTOP expression and prognosis and explored its role in the malignant behaviors of epithelial ovarian cancer cells. We found that higher expression of CHTOP was associated with a lower disease-free survival (DFS) rate in ovarian cancer patients. Also, CHTOP was highly expressed in human ovarian cancer tissues compared with normal and adjacent tissues. Moreover, compared with IGROV-1 cell line, higher expression of CHTOP was also confirmed in the malignant ovarian cancer cell lines (OV-90 and SK-OV-3). Further results from wound-healing and Matrigel assay showed that CHTOP knockdown significantly reduced the migration and invasion ability of OV-90 and SK-OV-3 cells, while colony formation assay and apoptosis detection showed that CHTOP knockdown markedly sensitized OV-90 and SK-OV-3 cells to cisplatin treatment by inducing apoptosis. Additionally, CHTOP silence also remarkably weakened the stemness of OV-90 and SK-OV-3 through inhibiting the protein expressions of several transcriptional or surface markers of cancer stem cells. These findings first suggest that CHTOP, as a highly expressed protein in ovarian cancer, is closely associated with the malignant phenotypes of epithelial ovarian cancer cells, including metastasis, chemoresistance, and stemness, which highlights a promising role of CHTOP in ovarian cancer targeted therapy.

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Downregulation of SPINK13 Promotes Metastasis by Regulating uPA in Ovarian Cancer Cells

Cited by 20 publications

References 39 publications

Circulating uPA as a potential prognostic biomarker for resectable esophageal squamous cell carcinoma

Circulating uPA as a potential prognostic biomarker for resectable esophageal squamous cell carcinoma

The Inhibitory Effects of Recombinant Hespintor Combined with Sorafenib on Transplanted Human Hepatoma in Nude Mice, and Transcriptional Regulation of Hespintor Based on RNA-Seq

Chromatin target of protein arginine methyltransferase regulates invasion, chemoresistance, and stemness in epithelial ovarian cancer

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