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.

CD20, generalidades básicas-moleculares y su posible relación como marcador de mal pronóstico en leucemia / CD20, basic-molecular generalities, and its possible relationship as a marker of poor prognosis in leukemia

CD20 es una proteína transmembranal expresada en la superficie del linfocito B y desempeña un papel muy importante en su desarrollo y diferenciación. Se expresa en la gran mayoría de neoplasias de células B, como en la leucemia linfoblástica aguda (LLA). Se recopiló información sobre la estructura biológica y molecular del marcador CD20 y su mecanismo de regulación, para mejorar el entendimiento sobre su función dentro de la célula, el efecto que ejerce como marcador de mal pronóstico cuando se encuentra expresado en pacientes adultos diagnosticados con LLA y las ventajas de ser utilizado como blanco terapéutico en esta patología.

CD20 is a transmembrane protein expressed on the surface of the B lymphocyte and plays a significant role in its development and differentiation. It is expressed in most B-cell neoplasms, such as Acute Lymphoblastic Leukemia (ALL). Information was collected on the biological and molecular structure of the CD20 marker and its regulation mechanism to improve the understanding of its function within the cell, the effect it exerts as a marker of poor prognosis when expressed in adult patients diagnosed with ALL, and the advantages of being used as a therapeutic target in this pathology.

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 E­cadherin, 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) Epigenetic­independent, including the induction of negative regulators of CDH1 expression, such as Snail family transcriptional repressor Snai1 and Snai2. To test this hypothesis, HPV16­ and HPV18­positive 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.

Prevalencia de los Genotipos del Virus del Papiloma Humano en mujeres de 25 a 65 años / Prevalence of Human Papillomavirus Genotypes in women aged 25 to 65 years

Introducción: La infección que ocasiona el Virus del Papiloma Humano (VPH), tiene alta prevalencia en mujeres sexualmente activas. Generalmente es pasajera, pero al existir algunos factores relacionados pueden llegar a desarrollar cáncer cervicouterino. Dado que la enfermedad se desarrolla con lentitud la detección en etapas tempranas ha permitido poner en evidencia la presencia del virus en las células antes que puedan transformarse y volverse tumorigénicas. El objetivo de este estudio fue establecer la prevalencia de los genotipos del Virus del Papiloma Humano en mujeres de 25 a 65 años en un grupo de pacientes de un centro oncológico en Cuenca 2017 ­2018. Métodos:Es un estudio descriptivo, retrospectivo, analítico, en el cual se recopiló información de las historias clínicas y registros físicos del Laboratorio de Biología Molecular y del sistema médico de SOLCA -Cuenca, SOFTCASE, para establecer la prevalencia de VPH durante el periodo 2017 -2018.Se utiliza ODDS Ratio para demostrar asociación entre las variables demográficas y los grupos de serología de VPH de riesgo alto versus VPH De riesgo bajo. Resultados:Se incluyeron 594casos, con edad entre36 y 40 años n=103/594 (17.3%). De estado civil casadas n=318/594 (53.5%). Con paridad igual a 2 n=159/594 (26.8%). Casospositivos de VPH fueron 424/594 (71.38%) IC95% (71.23% a 71.53%), Genotipos de alto riesgo con el 58.01%, genotipos de probable bajo riesgo con el 33.25% y genotipos de bajo riesgo 8.72%. La prevalencia del 50% de la población positiva según el genotipo lo explicalos VPH 16, 71, 58, 6 y 31. De este grupo los VPH con serología 16, 58 y 31 tienen un riesgo Alto de malignidad. No se reportó asociación entre los VPH de alto riesgo con alguna de las variables demográficas. Conclusión:El grupo etario con mayor número de casos positivos perteneció a las mujeres de entre 36 y 40 años de edad, con paridad igual a 2 y de estado civil casadas. El subtipo VPH-16 fue el genotipo más prevalente del grupo de alto riesgo de malignidad. El subtipo VPH-71 fue el segundo genotipo más prevalente con un perfil de probable bajo riesgo de malignidad.

AbstractIntroduction:The infection caused by the Human Papilloma Virus (HPV) has a high prevalence in sexually active women. It is generally temporary, but when there are some related factors, they can develop cervical cancer. Since the disease develops slowly, detection in early stages has made it possible to reveal the presence of the virus in cells before they can transform and become tumorigenic. The objective of this study was to establish the prevalence of Human Papilloma Virus genotypes in women aged 25 to 65 years in a group of patients from an oncology center in Cuenca 2017-2018. Methods: It is a descriptive, retrospective, analytical study, in which information was collected from the medical records and physical records of the Molecular Biology Laboratory and the SOLCA -Cuenca medical system, SOFTCASE, to establish the prevalence of HPV during the period 2017 -2018. ODDS Ratio is used to demonstrate association between demographic variables and high-risk HPV versus low-risk HPV serology groups. Results: 594 cases were included, aged between 36 and 40 years, n = 103/594 (17.3%). Marital status married n = 318/594 (53.5%). With parity equal to 2 n = 159/594 (26.8%). Positive HPV cases were 424/594 (71.38%) 95% CI (71.23% to 71.53%), high risk genotypes with 58.01%, probable low risk genotypes with 33.25% and low risk genotypes 8.72%. The prevalence of 50% of the positive population according to genotype is explained by HPV 16, 71, 58, 6 and 31. Of this group, HPV with serology 16, 58 and 31 have a high risk of malignancy. No association was reported between high-risk HPV with any of the demographic variables. Conclusion: The age group with the highest number of positive cases belonged to women between 36 and 40 years of age, with parity equal to 2 and married marital status. The HPV-16 subtype was the most prevalent genotype in the group at high risk of malignancy. The HPV-71 subtype was the second most prevalent genotype with a profile of probable low risk of malignancy.

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

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.