Inhibition of cervical cancer cell growth by human papillomavirus virus–like particles packaged with human papillomavirus oncoprotein short hairpin RNAs

Abstract

Overexpression of human papillomavirus (HPV E6 and HPV E7) oncogenes in human cervical cells results in the development of cancer, and E6 and E7 proteins are therefore targets for preventing cervical cancer progression. Here, we describe the silencing of E6 and E7 expression in cervical carcinoma cells by RNA interference. In order to increase the efficacy of the RNA interference, HPV pseudovirions coding for a short hairpin RNA (shRNA) sequence were produced. The results indicated the degradation of E6 and E7 mRNAs when shRNA against E6 or E7 were delivered by pseudovirions in HPV-positive cells (CaSki and TC1 cells). E6 silencing resulted in the accumulation of cellular p53 and reduced cell viability. More significant cell death was observed when E7 expression was suppressed. Silencing E6 and E7 and the consequences for cancer cell growth were also investigated in vivo in mice using the capacity of murine TC1 cells expressing HPV-16 E6 and E7 oncogenes to induce fast-growing tumors. Treatment with lentiviruses and HPV virus-like particle vectors coding for an E7 shRNA sequence both resulted in dramatic inhibition of tumor growth. These results show the ability of pseudovirion-delivered shRNA to produce specific gene suppression and provide an effective means of reducing HPV-positive tumor growth. [Mol Cancer Ther 2009; 8(2):357 -65]

IGF axis and other factors in HPV-related and HPV-unrelated carcinogenesis (Review)

“…The presence of L1 capsids can also induce local immunization against L1 neutralizing epitopes, thus conferring protection in cases of HPV reinfection after the death of E7-expressing cells. These pseudovirions represent a new step in designing rational molecular cancer therapy using RNA interference, at the same time, offering protection against reinfection by the causative agent of cervical cancer (116). Another new active targeted immunotherapeutic has been evaluated, Modified Vaccinia Virus Ankara (MVA) vector, containing the E1 sequence of HPV-16, aimed at inducing cellular immune responses with potential to help and clear persistent HPV-16-related infection.…”

Effects of HMGB1 expression suppressed by siRNA on cell cycle and proliferation of human cervical cancer cell line HeLa

“…The generation of cervical cancer is a complex process which multi-steps and multigenes are involved in [5] . In recent years, an increasing number of oncogenes related to the incidence, invasion, and metastasis of cervical cancer have been discovered, such as P53, bcl-2, survin, HPV E6 and E7 [6,7] . HMGB1 was discovered as a multifunctional cytokine involved in the growth, invasion, metastasis, clinical stage and prognosis of pancreatic cancer [8] , liver cancer, gastric cancer, melanoma, colon cancer [9] , breast cancer, bile duct cancer, and prostate cancer.…”

Oligonucleotide Applications for the Therapy and Diagnosis of Human Papillomavirus Infection

“…Although many reports have established the feasibility of this approach (Bai et al, 2006;Bousarghin et al, 2009;Gu et al, 2011), it is clear that prolonged siRNA expression may lead to dysfunction of the RNAi pathway (Tang et al, 2006) or other intracellular effects (Koivusalo et al, 2006) due to the sudden rise in p53 and pRB proteins after siRNA treatment (Sima et al, 2008). Thus, siRNA treatment has been used to enhance already established therapies for cervical cancer such as paclitaxel (Liu et al, 2009), cisplatin (Wu et al, 2011) and TRAIL (Eaton et al, 2011) with sometimes mixed results depending on the condition of p53 expression (Koivusalo et al, 2005).…”