Small interfering RNA against PTTG: A novel therapy for ovarian cancer

Abstract

Abstract. Ovarian epithelial cancer is a significant cause of death among women, accounting for 5% of all female cancer-related fatalities. A lack of reliable detection methods and resistance to chemotherapy agents are considerable obstacles in the treatment of this cancer. Recently, high-level expression of the pituitary tumor transforming gene (PTTG) was found in a wide range of tumors, including ovarian cancers. Elevated PTTG levels were found to induce cellular transformation in vitro and tumor formation in nude mice. Therefore, we hypothesize a correlation exists between the levels of PTTG expression and tumorigenesis, and that downregulation of PTTG levels will result in the suppression of tumor growth. We used small interfering RNA (siRNA) to silence PTTG expression in human A2780 ovarian carcinoma cells and assessed the effect of PTTG silencing in tumor formation in vitro and in vivo. The siRNA directed against PTTG reduced its expression at both the mRNA and protein levels. A fifty percent reduction in cell proliferation was achieved in cells constitutively expressing PTTG siRNA compared to vector or control-siRNA transfected cells. Furthermore, colony formation in soft agar was reduced by 70% in PTTG siRNA stable cell lines. Using nude mice, we showed that animals injected with A2780 cells constitutively expressing PTTG-siRNA decreased the incidence of tumor development and tumor growth. Taken together, these results strongly suggest that PTTG may serve as an important molecular target for the discovery of new anticancer agents and treatment strategies.

Altered eIF6 and Dicer expression is associated with clinicopathological features in ovarian serous carcinoma patients

“…Many research groups demonstrate a functional interfering RNA pathway in ovarian adenocarcinoma cell lines by using small interfering RNA constructs targeting mRNAs. 55,56 In addition, global microRNA profiling has showed that Drosha overexpression in cervical squamous cell carcinoma appears to be of functional significance. 57 However, despite evidence for decreased Dicer levels leading to a decrease in microRNA let -7, 7 no definitive evidence linking global alterations in microRNA profiles to Dicer levels has been demonstrated to date.…”

Expression of Pituitary Tumor Transforming Gene 1 is an Independent Factor of Poor Prognosis in Localized or Locally Advanced Prostate Cancer Cases Receiving Hormone Therapy

“…Overexpression of PTTG1 enhances the cell proliferation, migration, invasion, and/or tumorigenicity and the induction of aneuploidy of cells derived from cancers of the human pituitary, kidney, esophagus, breast, head, and neck, liver, thyroid, lung, etc (Solbach et al, 2004;Zhou et al, 2005;Kim et al, 2006;Malik and Kakar, 2006;Rehfeld et al, 2006;Solbach et al, 2006;Wuttig et al, 2009;Liang et al, 2011). PTTG1 overexpression correlates with metastasis and poor overall survival in various human cancers (Heaney et al, 2000;Malik and Kakar, 2006;Wuttig et al, 2009), and decreasing PTTG expression through PTTG siRNA inhibits tumor growth in ovarian (El-Naggar et al, 2007), hepatic (Cho-Rok et al, 2006). And lung cancer cell lines, indicating that PTTG1 may be a new therapeutic target for cancer treatment.…”

Development of pituitary tumor-transforming gene (PTTG) transgenic mice for the treatment of ovarian cancer.

“…This study showed that by using the MISIIR promoter, 3 different tissues could be targeted: OSE, granulosa cells, and pituitary. However, possibly due to the weak expression of PTTG, the animals failed to generate any visible tumors, as the amount of expression is critical in ectopic tumor progression [116].…”

“…As PTTG has also been indentified in ovarian cancer taken from patients at the time of surgical resectioning [116], we wanted to identify the in vivo tumorigenic potential of PTTG through the development of a transgenic mouse model that could faithfully represent spontaneous EOC found in patients through the strong, non-specific overexpression of PTTG using the CMV promoter.…”

“…PTTG is an oncogene involved in pituitary carcinogenesis [lIS] and is overexpressed in ovarian cancer [116]. In a previous attempt to generate an ovarian cancer model representative of EOC, PTTG was placed under the control ofMISIIR in an effort to target it to the ovarian surface epithelium [130].…”