A Novel Role of Connective Tissue Growth Factor in the Regulation of the Epithelial Phenotype.

BACKGROUND: Epithelial-mesenchymal transition (EMT) is a biological process where epithelial cells lose their adhesive properties and gain invasive, metastatic, and mesenchymal properties. Maintaining the balance between the epithelial and mesenchymal stage is essential for tissue homeostasis. Many of the genes promoting mesenchymal transformation have been identified; however, our understanding of the genes responsible for maintaining the epithelial phenotype is limited. Our objective was to identify the genes responsible for maintaining the epithelial phenotype and inhibiting EMT. METHODS: RNA seq was performed using an vitro model of EMT. CTGF expression was determined via qPCR and Western blot analysis. The knockout of CTGF was completed using the CTGF sgRNA CRISPR/CAS9. The tumorigenic potential was determined using NCG mice. RESULTS: The knockout of CTGF in epithelial ovarian cancer cells leads to the acquisition of functional characteristics associated with the mesenchymal phenotype such as anoikis resistance, cytoskeleton remodeling, increased cell stiffness, and the acquisition of invasion and tumorigenic capacity. CONCLUSIONS: We identified CTGF is an important regulator of the epithelial phenotype, and its loss is associated with the early cellular modifications required for EMT. We describe a novel role for CTGF, regulating cytoskeleton and the extracellular matrix interactions necessary for the conservation of epithelial structure and function. These findings provide a new window into understanding the early stages of mesenchymal transformation.

A Trans-Ethnic Genome-Wide Association Study of Uterine Fibroids.

Uterine fibroids affect up to 77% of women by menopause and account for up to $34 billion in healthcare costs each year. Although fibroid risk is heritable, genetic risk for fibroids is not well understood. We conducted a two-stage case-control meta-analysis of genetic variants in European and African ancestry women with and without fibroids classified by a previously published algorithm requiring pelvic imaging or confirmed diagnosis. Women from seven electronic Medical Records and Genomics (eMERGE) network sites (3,704 imaging-confirmed cases and 5,591 imaging-confirmed controls) and women of African and European ancestry from UK Biobank (UKB, 5,772 cases and 61,457 controls) were included in the discovery genome-wide association study (GWAS) meta-analysis. Variants showing evidence of association in Stage I GWAS (P < 1 × 10-5) were targeted in an independent replication sample of African and European ancestry individuals from the UKB (Stage II) (12,358 cases and 138,477 controls). Logistic regression models were fit with genetic markers imputed to a 1000 Genomes reference and adjusted for principal components for each race- and site-specific dataset, followed by fixed-effects meta-analysis. Final analysis with 21,804 cases and 205,525 controls identified 326 genome-wide significant variants in 11 loci, with three novel loci at chromosome 1q24 (sentinel-SNP rs14361789; P = 4.7 × 10-8), chromosome 16q12.1 (sentinel-SNP rs4785384; P = 1.5 × 10-9) and chromosome 20q13.1 (sentinel-SNP rs6094982; P = 2.6 × 10-8). Our statistically significant findings further support previously reported loci including SNPs near WT1, TNRC6B, SYNE1, BET1L, and CDC42/WNT4. We report evidence of ancestry-specific findings for sentinel-SNP rs10917151 in the CDC42/WNT4 locus (P = 1.76 × 10-24). Ancestry-specific effect-estimates for rs10917151 were in opposite directions (P-Het-between-groups = 0.04) for predominantly African (OR = 0.84) and predominantly European women (OR = 1.16). Genetically-predicted gene expression of several genes including LUZP1 in vagina (P = 4.6 × 10-8), OBFC1 in esophageal mucosa (P = 8.7 × 10-8), NUDT13 in multiple tissues including subcutaneous adipose tissue (P = 3.3 × 10-6), and HEATR3 in skeletal muscle tissue (P = 5.8 × 10-6) were associated with fibroids. The finding for HEATR3 was supported by SNP-based summary Mendelian randomization analysis. Our study suggests that fibroid risk variants act through regulatory mechanisms affecting gene expression and are comprised of alleles that are both ancestry-specific and shared across continental ancestries.

Differential gene expression induced by Verteporfin in endometrial cancer cells.

Endometrial cancer (EMCA) is a clinically heterogeneous disease. Previously, we tested the efficacy of Verteporfin (VP) in EMCA cells and observed cytotoxic and anti-proliferative effects. In this study, we analyzed RNA sequencing data to investigate the comprehensive transcriptomic landscape of VP treated Type 1 EMCA cell lines, including HEC-1-A and HEC-1-B. There were 549 genes with differential expression of two-fold or greater and P < 0.05 after false discovery rate correction for the HEC-1-B cell line. Positive regulation of TGFß1 production, regulation of lipoprotein metabolic process, cell adhesion, endodermal cell differentiation, formation and development, and integrin mediated signaling pathway were among the significantly associated terms. A functional enrichment analysis of differentially expressed genes after VP treatment revealed extracellular matrix organization Gene Ontology as the most significant. CDC23 and BUB1B, two genes crucially involved in mitotic checkpoint progression, were found to be the pair with the best association from STRING among differentially expressed genes in VP treated HEC-1-B cells. Our in vivo results indicate that subcutaneous tumors in mice were regressed after VP treatment by inhibiting cell cycle pathway proteins. The present study revealed multiple key genes of pathological significance in EMCA, thereby improving our understanding of molecular profiles of EMCA cells.

Cervical Cancer Patients' Willingness and Ability to Serve as Health Care Educators to Advocate for Human Papillomavirus Vaccine Uptake.

Human papillomavirus (HPV) causes nearly all cervical cancer. Only half of females and less than half of males receive the recommended HPV vaccine dose. This study explores whether cervical cancer patients may serve as health advocates to adolescents and their parents in encouraging the uptake of the HPV vaccine. The study targeted an opportunity sample of women seen in the gynecology oncology clinic with a diagnosis of cervical cancer. During interviews, patients were asked about the following: provider conversations regarding cervical cancer, knowledge of HPV and the vaccine, discussions with family or friends about the causes or prevention of cervical cancer, and whether they would be willing to talk with others about the HPV vaccine. Twenty-three interviews were conducted in 2016-2017. Patients ranged from 28 to 61 years of age. Four team members developed a coding list, then used these themes to code the interviews. Six themes resulted from the analysis of the transcripts: (1) Expressions of fears, questioning effectiveness of vaccine; (2) Low level of health literacy; (3) Acquiring health information from television, internet; (4) Provider conversations (with patients regarding HPV and the vaccine); (5) Patient stigma surrounding cervical cancer; (6) Patients' willingness to serve as a health care educator. While cervical cancer patients overall expressed a willingness to serve as health care educators, barriers remain. Low health literacy and a lack of understanding of the causes of cervical cancer persist. These issues will need to be addressed in order for cervical cancer patients to be effective advocates.

Malignant Brenner tumor: Two case reports.

Malignant Brenner tumor (MBT) is a rare ovarian tumor that, given the infrequency of the disease, has not been well documented in the literature. Diagnosing MBT both radiographically and histologically remains a challenge. We report two cases of ovarian MBT, detailing the clinical presentation, radiographic characteristics, and histologic findings with supplementary imaging. Our cases demonstrate the pathologic challenge of histologically diagnosing MBT versus other Brenner tumors and transitional cell carcinoma (TCC) of the ovary.

Evaluation of Society of Gynecologic Oncologists (SGO) ovarian cancer quality surgical measures.

OBJECTIVES: The Society of Gynecologic Oncologists has developed two measures to assess and improve the surgical care of patients with ovarian cancer (1) description of residual disease following cytoreduction and (2) adequacy of surgical staging. Our aim was to establish baseline surgeon compliance with these two measures. METHODS: A retrospective review of patients with ovarian, fallopian tube or peritoneal cancer undergoing surgery between 7/1/2006 and 7/1/2011 for the purposes of staging and/or cytoreduction was performed at the University of Washington and Geisinger Medical Center. Operative and pathology reports were reviewed to obtain information pertaining to stage, histology, residual disease after surgery and the extent of surgical staging. RESULTS: 537 cases were identified; 91% with ovarian cancer. 61% of patients had at least stage IIIC disease; 15% had recurrent disease and 16% had neoadjuvant therapy. For patients with stages I-IIIB disease, 74% had full surgical staging, 10% did not have full surgical staging but documented the reason for this in the operative report; 15% did not have full surgical staging, no reason was noted. 25% of all operative reports lacked documentation of residual disease with 40% documenting no gross residual disease, 18% with residual disease <1cm and 18% had suboptimal debulking with >1 cm disease remaining. There was a statistically significant increase in appropriate documentation of amount of residual disease over time (p<0.001). CONCLUSIONS: Our study sets benchmarks for evaluation of documentation in gynecologic oncology centers. Improved documentation and staging will allow for equivalent standards of care across institutions.