scholarly journals Infection by High-Risk Human Papillomaviruses, Epithelial-to-Mesenchymal Transition and Squamous Pre-Malignant or Malignant Lesions of the Uterine Cervix: A Series of Chained Events?

2021 ◽  
Vol 22 (24) ◽  
pp. 13543
Author(s):  
Giovanni Barillari ◽  
Roberto Bei ◽  
Vittorio Manzari ◽  
Andrea Modesti
Keyword(s):  
High Risk ◽  
Uterine Cervix ◽  
Epithelial To Mesenchymal Transition ◽  
Cervical Squamous Cell Carcinoma ◽  
Human Papillomaviruses ◽  
Mesenchymal Transition ◽  
Malignant Lesions ◽  
Hpv Oncoproteins ◽  
The Many ◽  
The Impact

Wound healing requires static epithelial cells to gradually assume a mobile phenotype through a multi-step process termed epithelial-to-mesenchymal transition (EMT). Although it is inherently transient and reversible, EMT perdures and is abnormally activated when the epithelium is chronically exposed to pathogens: this event deeply alters the tissue and eventually contributes to the development of diseases. Among the many of them is uterine cervical squamous cell carcinoma (SCC), the most frequent malignancy of the female genital system. SCC, whose onset is associated with the persistent infection of the uterine cervix by high-risk human papillomaviruses (HR-HPVs), often relapses and/or metastasizes, being resistant to conventional chemo- or radiotherapy. Given that these fearsome clinical features may stem, at least in part, from the exacerbated and long-lasting EMT occurring in the HPV-infected cervix; here we have reviewed published studies concerning the impact that HPV oncoproteins, cellular tumor suppressors, regulators of gene expression, inflammatory cytokines or growth factors, and the interactions among these effectors have on EMT induction and cervical carcinogenesis. It is predictable and desirable that a broader comprehension of the role that EMT inducers play in SCC pathogenesis will provide indications to flourish new strategies directed against this aggressive tumor.

scholarly journals Clinical Significance of the Interaction between Human Papillomavirus (HPV) Type 16 and Other High-Risk Human Papillomaviruses in Women with Cervical Intraepithelial Neoplasia (CIN) and Invasive Cervical Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Arsenio A. Spinillo ◽  
Mattia M. Dominoni ◽  
Anna A. C. Boschi ◽  
Cecilia C. Sosso ◽  
Giacomo G. Fiandrino ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
High Risk ◽  
Residual Disease ◽  
Invasive Cervical Cancer ◽  
Intraepithelial Neoplasia ◽  
Human Papillomaviruses ◽  
Multiple Infections ◽  
Cervical Lesions ◽  
Hpv 16 ◽  
The Impact

The aim is to evaluate the clinical consequences of coinfection between HPV 16 and other high-risk HPVs among women with a histological diagnosis of CIN or invasive cervical cancer. A total of 2985 women, with a diagnosis of either CIN or cancer (<IB) on cervical or cone biopsy, were included. HPV genotypes were identified using the INNO-LiPA HPV genotyping assay, version EXTRA, on cervical scraping, before the colposcopic evaluation and the colposcopic biopsies or conization. In the overall population, HPV16 interacted positively with HPV18 (RR = 2, 95% CI 1.5–2.6) and negatively with HPV33, 51, 52, and 66, in log-linear analysis. There was an excess of CIN3 diagnoses among subjects coinfected with HPV16 and HPV18 or HPV52, although the absolute number of cases was relatively small. In a logistic model, the odds ratio of CIN3+ associated with coinfection of HPV16 and HPV18 (OR = 3.8, 95% CI 2.5–5.7, p = 0.004 compared to single HPV16) or HPV52 (OR = 3.6, 95% CI 2.6–5.1, p = 0.009 compared to single HPV) was higher than that associated with single HPV 16 infections. Finally, multiple infections had no effect on residual disease and did not influence the recurrence of high-grade CIN during a median follow-up of 25 months (IR 17–41). HPV16 interacted positively with HPV18 and negatively with HPV33, 51, 52, and 66 supporting the notion that HPV16 interacts mostly negatively with other HR-HPVs in CIN lesions. Among specimens coinfected with HPV16 and 18 or 52, there was an excess of CIN3+ although the impact on the prevalence of severe cervical lesions was limited.

Betulinic acid suppresses NGAL-induced epithelial-to-mesenchymal transition in melanoma

2013 ◽  
Vol 394 (6) ◽  
pp. 773-781 ◽  
Author(s):  
Dorina Gheorgheosu ◽  
Michaela Jung ◽  
Bilge Ören ◽  
Tobias Schmid ◽  
Cristina Dehelean ◽  
...  
Keyword(s):  
Betulinic Acid ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Melanoma Cells ◽  
Antitumoral Activity ◽  
Cellular Phenotype ◽  
Mesenchymal Transition ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Neutrophil Gelatinase ◽  
The Impact

Abstract Betulinic acid (BA) exhibits antitumoral activity by blocking proliferation, invasion, and angiogenesis. However, the impact of BA on epithelial-to-mesenchymal transition (EMT), a hallmark of cancer metastasis induced among others by neutrophil gelatinase-associated lipocalin (NGAL), remains unknown. The present study aimed at determining the effect of BA on NGAL-induced EMT. In A375 melanoma cells, BA downregulated mesenchymal markers, increased epithelial markers, and inhibited cytoskeletal reorganization. In addition, BA limited endogenous NGAL production and further suppressed EMT induced by exogenously added NGAL and the corresponding invasive cellular phenotype. In conclusion, BA interferes with EMT-associated changes, a mechanism to antagonize invasive melanoma cells.

scholarly journals Hypoxia-induced alternative splicing: the 11th Hallmark of Cancer

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Antonietta Rosella Farina ◽  
Lucia Cappabianca ◽  
Michela Sebastiano ◽  
Veronica Zelli ◽  
Stefano Guadagni ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Tumour Cell ◽  
Epithelial To Mesenchymal Transition ◽  
Tumour Progression ◽  
Protein Isoforms ◽  
Metastatic Progression ◽  
Mesenchymal Transition ◽  
Cell Immortalization ◽  
Oncogene Activation ◽  
The Many

Abstract Hypoxia-induced alternative splicing is a potent driving force in tumour pathogenesis and progression. In this review, we update currents concepts of hypoxia-induced alternative splicing and how it influences tumour biology. Following brief descriptions of tumour-associated hypoxia and the pre-mRNA splicing process, we review the many ways hypoxia regulates alternative splicing and how hypoxia-induced alternative splicing impacts each individual hallmark of cancer. Hypoxia-induced alternative splicing integrates chemical and cellular tumour microenvironments, underpins continuous adaptation of the tumour cellular microenvironment responsible for metastatic progression and plays clear roles in oncogene activation and autonomous tumour growth, tumor suppressor inactivation, tumour cell immortalization, angiogenesis, tumour cell evasion of programmed cell death and the anti-tumour immune response, a tumour-promoting inflammatory response, adaptive metabolic re-programming, epithelial to mesenchymal transition, invasion and genetic instability, all of which combine to promote metastatic disease. The impressive number of hypoxia-induced alternative spliced protein isoforms that characterize tumour progression, classifies hypoxia-induced alternative splicing as the 11th hallmark of cancer, and offers a fertile source of potential diagnostic/prognostic markers and therapeutic targets.

Ras and C-Myc Oncoproteins during Tumor Progression in the Uterine Cervix

1998 ◽  
Vol 84 (5) ◽  
pp. 583-588 ◽  
Author(s):  
Sivakumari Asha Nair ◽  
Madhavan Balaraman Nair ◽  
Puthuveetil Govindan Jayaprakash ◽  
Thayyullathil Nellika Rajalekshmy ◽  
Madhavan Krishnan Nair ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Uterine Cervix ◽  
Mean Value ◽  
Low Grade ◽  
Cervical Tissue ◽  
Ras Gene ◽  
Tissue Samples ◽  
Cervical Epithelium ◽  
Malignant Lesions ◽  
The Many

Aims and background Altered oncogenic activity is a feature associated with many malignant and premalignant conditions. Among the many oncogenes, ras and myc are commonly altered in many tumors. This study aims to evaluate the expression of ras and c-myc oncoproteins in a total of 204 cervical tissue samples, including premalignant and malignant lesions as well as apparently normal cervical tissue. Methods and study design Mouse monoclonal antibodies against the three mammalian ras gene products (c-H-ras, c-K-ras, c-N-ras) and the c-myc protein were used to evaluate oncoprotein expression by immunocytochemistry. Results None of the samples analyzed displayed immunoreactivity for H-ras and K-ras. Normal cervical epithelium showed minimal immunoreactivity for N-ras with about 33% of the samples expressing the protein. More conspicuous expression in normal tissue was displayed by c-myc, with about 90% of the samples expressing the protein (mean value of cells positive = 34%). The immunoreactivity for N-ras increased with increasing histological abnormality from low-grade squamous intraepithelial lesions (SIL) to invasive carcinoma. Increased immunoreactivity for N-ras was evident in the basaloid cells of malignant lesions, with the maximum value of 66% found in poorly differentiated squamous cell carcinoma (PDSCC). The percentage of nuclei positive for c-myc also showed a gradual increase from low-grade SIL onwards, the highest positivity being found in PDSCC, where the mean value was 85%. Statistical analysis revealed a good correlation between the expression of N-ras (r = 0.8922, P = 0.001) and c-myc (r = 0.8856, P =0.001) and various histological stages of tumor progression in the cervical epithelium. Conclusions These results therefore suggest that c-myc and N-ras oncoproteins are important during tumor progression in the uterine cervix.

scholarly journals Epithelial-to-Mesenchymal Transition Mediates Docetaxel Resistance and High Risk of Relapse in Prostate Cancer

2014 ◽  
Vol 13 (5) ◽  
pp. 1270-1284 ◽  
Author(s):  
Mercedes Marín-Aguilera ◽  
Jordi Codony-Servat ◽  
Òscar Reig ◽  
Juan José Lozano ◽  
Pedro Luis Fernández ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Docetaxel Resistance ◽  
Risk Of Relapse

scholarly journals Epithelial and Mesenchymal Markers in Adrenocortical Tissues: How Mesenchymal Are Adrenocortical Tissues?

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1736
Author(s):  
Iuliu Sbiera ◽  
Stefan Kircher ◽  
Barbara Altieri ◽  
Martin Fassnacht ◽  
Matthias Kroiss ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Clinical Markers ◽  
Positive Role ◽  
Tissue Samples ◽  
Mesenchymal Transition ◽  
Epithelial Markers ◽  
Epithelial Cancers ◽  
Adrenocortical Adenomas ◽  
Slug Expression ◽  
The Impact

A clinically relevant proportion of adrenocortical carcinoma (ACC) cases shows a tendency to metastatic spread. The objective was to determine whether the epithelial to mesenchymal transition (EMT), a mechanism associated with metastasizing in several epithelial cancers, might play a crucial role in ACC. 138 ACC, 29 adrenocortical adenomas (ACA), three normal adrenal glands (NAG), and control tissue samples were assessed for the expression of epithelial (E-cadherin and EpCAM) and mesenchymal (N-cadherin, SLUG and SNAIL) markers by immunohistochemistry. Using real-time RT-PCR we quantified the alternative isoform splicing of FGFR 2 and 3, another known indicator of EMT. We also assessed the impact of these markers on clinical outcome. Results show that both normal and neoplastic adrenocortical tissues lacked expression of epithelial markers but strongly expressed mesenchymal markers N-cadherin and SLUG. FGFR isoform splicing confirmed higher similarity of adrenocortical tissues to mesenchymal compared to epithelial tissues. In ACC, higher SLUG expression was associated with clinical markers indicating aggressiveness, while N-cadherin expression inversely associated with these markers. In conclusion, we could not find any indication of EMT as all adrenocortical tissues lacked expression of epithelial markers and exhibited closer similarity to mesenchymal tissues. However, while N-cadherin might play a positive role in tissue structure upkeep, SLUG seems to be associated with a more aggressive phenotype.

scholarly journals Annexin A1 Is Required for Efficient Tumor Initiation and Cancer Stem Cell Maintenance in a Model of Human Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1154
Author(s):  
Cameron N. Johnstone ◽  
Yan Tu ◽  
Shenna Langenbach ◽  
David Baloyan ◽  
Andrew D. Pattison ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Human Breast Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Mrna Levels ◽  
Annexin A1 ◽  
Human Breast ◽  
Spontaneous Metastasis ◽  
Mesenchymal Transition ◽  
Patient Prognosis ◽  
The Impact

Triple-negative breast cancer (TNBC) has a poor outcome compared to other breast cancer subtypes, and new therapies that target the molecular alterations driving tumor progression are needed. Annexin A1 is an abundant multi-functional Ca2+ binding and membrane-associated protein. Reported roles of Annexin A1 in breast cancer progression and metastasis are contradictory. Here, we sought to clarify the functions of Annexin A1 in the development and progression of TNBC. The association of Annexin A1 expression with patient prognosis in subtypes of TNBC was examined. Annexin A1 was stably knocked down in a panel of human and murine TNBC cell lines with high endogenous Annexin A1 expression that were then evaluated for orthotopic growth and spontaneous metastasis in vivo and for alterations in cell morphology in vitro. The impact of Annexin A1 knockdown on the expression of genes involved in mammary epithelial cell differentia tion and epithelial to mesenchymal transition was also determined. Annexin A1 mRNA levels correlated with poor patient prognosis in basal-like breast tumors and also in the basal-like 2 subset of TNBCs. Unexpectedly, loss of Annexin A1 expression had no effect on either primary tumor growth or spontaneous metastasis of MDA-MB-231_HM xenografts, but abrogated the growth rate of SUM149 orthotopic tumors. In an MMTV-PyMT driven allograft model of breast cancer, Annexin A1 depletion markedly delayed tumor formation in both immuno-competent and immuno-deficient mice and induced epithelial to mesenchymal transition and upregulation of basal markers. Finally, loss of Annexin A1 resulted in the loss of a discrete CD24+/Sca1− population containing putative tumor initiating cells. Collectively, our data demonstrate a novel cell-autonomous role for Annexin A1 in the promotion of tumor-forming capacity in a model of human breast cancer and suggest that some basal-like TNBCs may require high endogenous tumor cell Annexin A1 expression for continued growth.

scholarly journals Human Papillomaviruses and Epstein–Barr Virus Interactions in Colorectal Cancer: A Brief Review

Pathogens ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 300 ◽  
Author(s):  
Queenie Fernandes ◽  
Ishita Gupta ◽  
Semir Vranic ◽  
Ala-Eddin Al Moustafa
Keyword(s):  
Colorectal Cancer ◽  
High Risk ◽  
Cancer Progression ◽  
Epstein Barr Virus ◽  
Human Papillomaviruses ◽  
Colorectal Carcinogenesis ◽  
Mesenchymal Transition ◽  
Barr Virus ◽  
Epstein Barr

Human papillomaviruses (HPVs) and the Epstein–Barr virus (EBV) are the most common oncoviruses, contributing to approximately 10%–15% of all malignancies. Oncoproteins of high-risk HPVs (E5 and E6/E7), as well as EBV (LMP1, LMP2A and EBNA1), play a principal role in the onset and progression of several human carcinomas, including head and neck, cervical and colorectal. Oncoproteins of high-risk HPVs and EBV can cooperate to initiate and/or enhance epithelial-mesenchymal transition (EMT) events, which represents one of the hallmarks of cancer progression and metastasis. Although the role of these oncoviruses in several cancers is well established, their role in the pathogenesis of colorectal cancer is still nascent. This review presents an overview of the most recent advances related to the presence and role of high-risk HPVs and EBV in colorectal cancer, with an emphasis on their cooperation in colorectal carcinogenesis.

scholarly journals Pooled CRISPR screening in pancreatic cancer cells implicates co-repressor complexes as a cause of multiple drug resistance via regulation of epithelial-to-mesenchymal transition

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ryne C. Ramaker ◽  
Andrew A. Hardigan ◽  
Emily R. Gordon ◽  
Carter A. Wright ◽  
Richard M. Myers ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Lines ◽  
Epithelial To Mesenchymal Transition ◽  
Cellular Migration ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells ◽  
Repressor Complex ◽  
Poor Outcomes ◽  
Multiple Drugs ◽  
The Impact

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) patients suffer poor outcomes, including a five-year survival of below 10%. Poor outcomes result in part from therapeutic resistance that limits the impact of cytotoxic first-line therapy. Novel therapeutic approaches are needed, but currently no targeted therapies exist to treat PDAC. Methods To assess cellular resistance mechanisms common to four cytotoxic chemotherapies (gemcitabine, 5-fluorouracil, irinotecan, and oxaliplatin) used to treat PDAC patients, we performed four genome-wide CRISPR activation (CRISPRact) and CRISPR knock-out (CRISPRko) screens in two common PDAC cell lines (Panc-1 and BxPC3). We used pathway analysis to identify gene sets enriched among our hits and conducted RNA-sequencing and chromatin immunoprecipitation-sequencing (ChIP-seq) to characterize top hits from our screen. We used scratch assays to assess changes in cellular migration with HDAC1 overexpression. Results Our data revealed activation of ABCG2, a well-described efflux pump, as the most consistent mediator of resistance in each of our screens. CRISPR-mediated activation of genes involved in transcriptional co-repressor complexes also conferred resistance to multiple drugs. Expression of many of these genes, including HDAC1, is associated with reduced survival in PDAC patients. Up-regulation of HDAC1 in vitro increased promoter occupancy and expression of several genes involved in the epithelial-to-mesenchymal transition (EMT). These cells also displayed phenotypic changes in cellular migration consistent with activation of the EMT pathway. The expression changes resulting from HDAC1 activation were also observed with activation of several other co-repressor complex members. Finally, we developed a publicly available analysis tool, PancDS, which integrates gene expression profiles with our screen results to predict drug sensitivity in resected PDAC tumors and cell lines. Conclusion Our results provide a comprehensive resource for identifying cellular mechanisms of drug resistance in PDAC, mechanistically implicate HDAC1, and co-repressor complex members broadly, in multi-drug resistance, and provide an analytical tool for predicting treatment response in PDAC tumors and cell lines.

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