Molecular iodine inhibits the expression of stemness markers on cancer stem-like cells of established cell lines derived from cervical cancer

Abstract Background Cancer stem cells (CSC) are characterized by deregulated self-renewal, tumorigenicity, metastatic potential, aberrant stemness signaling pathways, resistance to conventional therapy, and the ability to give rise to a progeny of proliferating cells that constitute the bulk of tumors. Targeting CSC will provide novel treatments for cancer. Different investigations have focused on developing complementary approaches that involve natural compounds that decrease chemo-resistance and reduce the side effects of conventional therapies. Since, it has been reported that molecular iodine (I2) exhibits antineoplastic effects and decreases tumor progression in some cancer models, we evaluated the potential effect of I2 on cell cultures enriched in cervical cancer stem-like cells. Methods HeLa and SiHa cervical cancer cells were treated with 200uM I2 for 24 h. After time, cells were cultured in CSC-conditioned medium (cervospheres) and viability assays were performed. Following, tumorigenic capabilities in cervospheres treated with I2 were evaluated in NOD/SCID mice. HeLa monolayer cells untreated and their respective cervosphere cells treated or untreated with 200 μM of I2 for 24 h were xenotransplanted subcutaneously at different amounts and mice were monitored for at least 2 months. Results In the present study, monolayer and CSC-enriched cultures (cervospheres) from cervical cancer-derived cell lines, HeLa and SiHa, showed that 200uM I2 supplementation inhibits proliferation of both and decreased their tumorigenic capacity, in vivo. This antineoplastic effect of I2 was accompanied by diminished expression of stemness markers including CD49f, CK17, OCT-4, NANOG, SOX2, and KLF4, as well as increased expression and activation of PPARγ receptors. Conclusions All this data led us to suggest a clinical potential use of I2 for targeting CSC and improve current treatments against cervical cancer

CDH1 and SNAI1 are regulated by E7 from human papillomavirus types 16 and 18

A common characteristic of cancer types associated with viruses is the dysregulated expression of the CDH1 gene, which encodes E‑cadherin, in general by activation of DNA methyltransferases (Dnmts). In cervical cancer, E7 protein from high risk human papillomaviruses (HPVs) has been demonstrated to interact with Dnmt1 and histone deacetylase type 1 (HDAC1). The present study proposed that E7 may regulate the expression of CDH1 through two pathways: i) Epigenetic, including DNA methylation; and ii) Epigenetic‑independent, including the induction of negative regulators of CDH1 expression, such as Snail family transcriptional repressor Snai1 and Snai2. To test this hypothesis, HPV16‑ and HPV18‑positive cell lines were used to determine the methylation pattern of the CDH1 promoter and its expression in association with its negative regulators. Different methylation frequencies were identified in the CDH1 promoter in HeLa (88.24%) compared with SiHa (17.65%) and Ca Ski (0%) cell lines. Significant differences in the expression of SNAI1 were observed between these cell lines, and an inverse association was identified between the expression levels of SNAI1 and CDH1. In addition, suppressing E7 not only increased the expression of CDH1, but notably decreased the expression of SNAI1 and modified the methylation pattern of the CDH1 promoter. These results suggested that the expression of CDH1 was dependent on the expression of SNAI1 and was inversely associated with the expression of E7. The present results indicated that E7 from HPV16/18 regulated the expression of CDH1 by the two following pathways in which Snai1 is involved: i) Hypermethylation of the CDH1 promoter region and increasing expression of SNAI1, as observed in HeLa; and ii) Hypomethylation of the CDH1 promoter region and expression of SNAI1, as observed in SiHa. Therefore, the suppression of CDH1 and expression of SNAI1 may be considered to be biomarkers of metastasis in uterine cervical cancer.The present study received additional support of the Fundación Miguel Alemán, A.C. to AGC. PRC received a fellowship from Programa de Movilidad Internacional de Estudiantes de la Coordinación de Estudios de Posgrado (CEP‑UNAM) during his doctoral stay at the Universidad Autónoma de Madrid (UAM).Peer reviewe

The Hallmarks of Cervical Cancer: Molecular Mechanisms Induced by Human Papillomavirus

Human papillomaviruses (HPVs) and, specifically, high-risk HPVs (HR-HPVs) are identified as necessary factors in the development of cancer of the lower genital tract, with CaCU standing out as the most prevalent tumor. This review summarizes ten mechanisms activated by HR-HPVs during cervical carcinogenesis, which are broadly associated with at least seven of the fourteen distinctive physiological capacities of cancer in the newly established model by Hanahan in 2022. These mechanisms involve infection by human papillomavirus, cellular tropism, genetic predisposition to uterine cervical cancer (CaCU), viral load, viral physical state, regulation of epigenetic mechanisms, loss of function of the E2 protein, deregulated expression of E6/E7 oncogenes, regulation of host cell protein function, and acquisition of the mesenchymal phenotype