Hepatocyte growth factor activator inhibitor-2 (HAI-2) is a favorable prognosis marker and inhibits cell growth through the apoptotic pathway in cervical cancer (original) (raw)
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Emerging Biological Treatments for Uterine Cervical Carcinoma
Journal of Cancer, 2014
Cervical cancer is the third most common cancer worldwide, and the development of new diagnosis, prognostic, and treatment strategies is a major interest for public health. Cisplatin, in combination with external beam irradiation for locally advanced disease, or as monotherapy for recurrent/metastatic disease, has been the cornerstone of treatment for more than two decades. Other investigated cytotoxic therapies include paclitaxel, ifosfamide and topotecan, as single agents or in combination, revealing unsatisfactory results. In recent years, much effort has been made towards evaluating new drugs and developing innovative therapies to treat cervical cancer. Among the most investigated molecular targets are epidermal growth factor receptor and vascular endothelial growth factor (VEGF) signaling pathways, both playing a critical role in cervical cancer development. Studies with bevacizumab or VEGF receptor tyrosine kinase have given encouraging results in terms of clinical efficacy, without adding significant toxicity. A great number of other molecular agents targeting critical pathways in cervical malignant transformation are being evaluated in preclinical and clinical trials, reporting preliminary promising data. In the current review, we discuss novel therapeutic strategies which are being investigated for the treatment of advanced cervical cancer.
Inhibitors of apoptosis proteins in human cervical cancer
BMC cancer, 2006
It has been shown that IAPs, in particular XIAP, survivin and c-IAP1, are overexpressed in several malignancies. In the present study we investigate the expression of c-IAP1, c-IAP2, XIAP and survivin and its isoforms in cervical cancer. We used semiquantitative RT-PCR assays to analyze 41 cancer and 6 normal tissues. The study included 8 stage I cases; 16 stage II; 17 stageIII; and a control group of 6 samples of normal cervical squamous epithelial tissue. c-IAP2 and XIAP mRNA levels were similar among the samples, cervical tumors had lower c-IAP1 mRNA levels. Unexpectedly, a clear positive association was found between low levels of XIAP and disease relapse. A log-rank test showed a significant inverse association (p = 0.02) between XIAP expression and tumor aggressiveness, as indicated by disease relapse rates. There were no statistically significant differences in the presence or expression levels of c-IAP1 and c-IAP2 among any of the clinical variables studied. Survivin and its...
Interleukin 2 (IL-2) has been used for the treatment of different types of cancer that express the IL-2 receptor (IL-2R). However, the effect of IL-2 on cervical cancer cells is unknown. IL-2R is present in normal cells of the immune system but not in the healthy cervix. We report that IL-2R is expressed in cervical cancer cells. IL-2 decreases cervical cancer cell proliferation via transient arrest of the G1 phase, which does not result in apoptosis or senescence. IL-2 upregulates the expression of p53 and p21 and downregulates cyclin D. In addition, we report the resistance of cervical cancer cells to treatments that induce apoptosis in HeLa and INBL cells. When arrested cells were treated with cisplatin, the cytokine protected cells from apoptosis induced by cisplatin. e effects of IL-2 on the cell cycle do not induce cellular senescence or activate the proapoptotic protein Bax. e cell arrest induced by IL-2 is conferring protection to cells against apoptosis.
Scientific Reports, 2019
Cervical cancer is the fourth most common cancer in women. Although cure rates are high for early stage disease, clinical outcomes for advanced, metastatic, or recurrent disease remain poor. To change this panorama, a deeper understanding of cervical cancer biology and novel study models are needed. Immortalized human cancer cell lines such as HeLa constitute crucial scientific tools, but there are few other cervical cancer cell lines available, limiting our understanding of a disease known for its molecular heterogeneity. This study aimed to establish novel cervical cancer cell lines derived from Brazilian patients. We successfully established one (HCB-514) out of 35 cervical tumors biopsied. We confirmed the phenotype of HCB-514 by verifying its' epithelial and tumor origin through cytokeratins, EpCAM and p16 staining. It was also HPV-16 positive. Whole-exome sequencing (WES) showed relevant somatic mutations in several genes including BRCA2, TGFBR1 and IRX2. A copy number variation (CNV) analysis by nanostring and WES revealed amplification of genes mainly related to kinases proteins involved in proliferation, migration and cell differentiation, such as EGFR, PIK3CA, and MAPK7. Overexpression of EGFR was confirmed by phospho RTK-array and validated by western blot analysis. Furthermore, the HCB-514 cell line was sensitive to cisplatin. In summary, this novel Brazilian cervical cancer cell line exhibits relevant key molecular features and constitutes a new biological model for pre-clinical studies. Cervical cancer is a major public health problem worldwide, making it the fourth most common type of cancer among women. In 2018, there were 570,000 new cases reported and 311,000 related deaths 1. Women between the ages of 50 and 60 years-old are most affected by cervical cancer 2. Persistent infection of the basal layer of cervical epithelium with high-risk human papillomavirus (
New molecular targets against cervical cancer
International Journal of Women's Health, 2014
Cervical cancer is the third most commonly diagnosed cancer worldwide and the fourth leading cause of cancer death in women. Major advances but still insufficient achievements in the treatment of locally advanced and high-risk early stage patients have occurred in the last decade with the incorporation of concurrent cisplatin with radiation and, lately, gemcitabine added to cisplatin chemoradiation. Despite a number of clinical studies incorporating moleculartargeted therapy as radiosensitizers being in progress, so far, only antiangiogenic therapy with bevacizumab added to cisplatin chemoradiation has demonstrated safety and shown encouraging results in a Phase II study. In advanced disease, cisplatin doublets do not have a great impact on the natural history of the disease with median survival rates not exceeding 13 months. The first Phase III study of bevacizumab, added to cisplatin or a non-cisplatin-containing doublet, showed significant increase in both overall survival and progression-free survival. Further studies are needed before bevacizumab plus chemotherapy can be considered the standard of care for advanced disease. Characterization of the mutational landscape of cervical cancer has already been initiated, indicating that, for now, few of these targetable alterations match with available agents. Progress in both the mutational landscape knowledge and developments of novel targeted therapies may result in more effective and individualized treatments for cervical cancer. The potential efficacy of knocking down the key alterations in cervical cancer-E6 and E7 human papillomavirus oncoproteins-must not be overlooked.
Oncogene, 2001
Histone deacetylase (HDAC) inhibitors sodium butyrate and trichostatin A arrest human papillomavirus (HPV)positive carcinoma cells in G1 to S transition of the cell cycle, which is paralleled by an up-regulation of the cyclin-dependent kinase inhibitors (CKIs) p21 CIP1 and p27 KIP1 as well as the complete loss of cdk2 activity. Although HPV expression was hitherto thought to be required to maintain a proliferative phenotype of these cells, cdk2 suppression is achieved even in the presence of ongoing viral transcription. While CKIs normally cannot exert their cdk2-inhibitory function in the presence of the viral oncoprotein E7, co-immunoprecipitation experiments revealed that E7 binding is prevented. Increase of p27 KIP1 correlates with down-regulation of p45 SKP2 , a component of the ubiquitin-protein ligase SCF SKP2 controlling the half-life of regulatory proteins during the cell cycle. HDAC inhibition also triggered an E7dependent degradation of pRb, while the levels of E2F remained unaected. The presence of free intracellular E2F and the concomitant up-regulation of CKIs during G1 arrest results in a`con¯icting growth situation', which ®nally renders the cells to undergo apoptosis. These data provide novel molecular insights into how the transforming potential of HPV can be bypassed and open new therapeutical perspectives for the treatment of cervical cancer. Oncogene (2001) 20, 4768 ± 4776.
HES1 Protein Modulates Human Papillomavirus–Mediated Carcinoma of the Uterine Cervix
Journal of Global Oncology, 2019
PURPOSE Cervical cancer (CC) is the most common cancer affecting women worldwide. Human papillomavirus (HPV) infection is a major contributing factor for the development of CC. The development of CC occurs progressively from precancer stages to cancerous stages (ie, invasive squamous cell carcinoma [ISCC] and adenocarcinoma [ADC]). ADC is a rare form of CC that develops from the mucinous endocervical epithelium. It is believed that the downstream targets of Notch signaling contribute to the etiology of CC. One such target is HES1, whose role in the modulation of ADC is unknown. The purpose of this study is to determine the role of HES1 protein in HPV-associated ADC subtype of CC and also to compare its expression in histologic subtypes of precancer and ISCC. PATIENTS AND METHODS A total of 148 patients (30 with precancers, 98 with ISCC, and 20 with ADC) and 40 normal control participants were analyzed for the expression of HES1 via immunohistochemistry, with results validated by imm...
HER2 expression in cervical cancer as a potential therapeutic target
BMC cancer, 2004
Trastuzumab, a humanized monoclonal antibody against the HER2 receptor is currently being used in breast and other tumor types. Early studies have shown that a variable proportion of cervical carcinoma tumors overexpress the HER2 receptor as evaluated by diverse techniques and antibodies. Currently it is known that a tumor response to trastuzumab strongly correlates with the level of HER2 expression evaluated by the Hercep Test, thus, it seems desirable to evaluate the status of expression of this receptor using the FDA-approved Hercep Test and grading system to gain insight in the feasibility of using trastuzumab in cervical cancer patients. We analyzed a series of cervical cancer cell lines, the primary tumors of 35 cases of cervical cancer patients and four recurrent cases, with the Hercep Test in order to establish whether this tumor type overexpress HER2 at level of 2+/3+ as trastuzumab is currently approved for breast cancer having such level of expression. The results indicat...