Abstract
The constitutive proliferation and resistance to differentiation and apoptosis of neoplastic cervical cells depend on sustained expression of human papillomavirus oncogenes. Inhibition of these oncogenes is a goal for the prevention of progression of HPV-induced neoplasias to cervical cancer. SiHa cervical cancer cells were transfected with an HPV-16 promoter reporter construct and treated with leukemia inhibitory factor (LIF), a human cytokine of the interleukin 6 superfamily. SiHa and CaSki cervical cancer cells were also assessed for proliferation by MTT precipitation, programmed cell death by flow cytometry, and HPV E6 and E7 expression by real-time PCR. LIF-treated cervical cancer cells showed significantly reduced HPV LCR activation, reduced levels of E6 and E7 mRNA, and reduced proliferation. We report the novel use of LIF to inhibit viral oncogene expression in cervical cancer cells, with concomitant reduction in proliferation suggesting re-engagement of cell-cycle regulation.
Highlights
Human Papillomavirus (HPV) is a necessary causative agent for cervical cancer [1, 2], the second most common cancer in women [3] and third overall cause of cancer mortality worldwide [4]
In order to verify that the observed decrease in long control region (LCR) transcription is functionally significant and not an artifact of the reporter system, we examined the effect of leukemia inhibitory factor (LIF) on mRNA expression by quantitative real-time PCR
In two unrelated cell lines, both HPV-16 transformed, LCRdependent transcription was significantly inhibited by LIF
Summary
Human Papillomavirus (HPV) is a necessary causative agent for cervical cancer [1, 2], the second most common cancer in women [3] and third overall cause of cancer mortality worldwide [4]. No approved, effective nonsurgical intervention for cervical dysplasia or for the underlying HPV infection exists. For localized and advanced localized cervical carcinoma, the concurrent administration of chemotherapy and radiation has been successful, if significantly toxic, but the treatment of recurrent and metastatic disease remains a challenge. Standard chemotherapy is generally palliative rather than curative, and there is limited experience with biologics in this group of patients; a new treatment modality is clearly needed. With over 13,000 cases of invasive cervical cancer, 50,000 cases of carcinoma in situ, and as many as 1,000,00 cases of cervical dysplasia diagnosed each year in the US alone, and with the majority of spending going to followup and treatment of neoplasia, a noninvasive treatment would have a tremendous effect on both women’s health and the financial burden of HPV
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