Long non-coding RNAs (lncRNAs) are emerging as regulators in cancer development and progression, and aberrant lncRNA profiles have been reported in several cancers. Here, we evaluated the potential of using the maternally expressed gene 3 (MEG3) tissue level as a prognostic marker in high-grade serous ovarian cancer (HGSOC), the most common and deadliest gynecologic malignancy. To the aim of the study, we measured MEG3 transcript levels in 90 pre-treatment peritoneal biopsies. We also investigated MEG3 function in ovarian cancer biology. We found that high MEG3 expression was independently associated with better progression-free (p = 0.002) and overall survival (p = 0.01). In vitro and in vivo preclinical studies supported a role for MEG3 as a tumor suppressor in HGSOC, possibly through modulation of the phosphatase and tensin homologue (PTEN) network. Overall, results from this study demonstrated that decreased MEG3 is a hallmark for malignancy and tumor progression in HGSOC.

A better understanding of locally advanced cervical cancer (LACC) is mandatory for further improving the rates of disease control, since a significant proportion of patients still fail to respond or undergo relapse after concurrent chemoradiation treatment (CRT), and survival for these patients has generally remained poor. To identify specific markers of CRT response, we compared pretreatment biopsies from LACC patients with pathological complete response (sensitive) with those from patients showing macroscopic residual tumor (resistant) after neoadjuvant CRT, using a proteomic approach integrated with gene expression profiling. The study of the underpinning mechanisms of chemoradiation response was carried out through in vitro models of cervical cancer. We identified annexin A2 (ANXA2), N-myc downstream regulated gene 1 (NDRG1) and signal transducer and activator of transcription 1 (STAT1) as biomarkers of LACC patients’ responsiveness to CRT. The dataset collected through qPCR on these genes was used as training dataset to implement a Random Forest algorithm able to predict the response of new patients to this treatment. Mechanistic investigations demonstrated the key role of the identified genes in the balance between death and survival of tumor cells. Our results define a predictive gene signature that can help in cervical cancer patient stratification, thus providing a useful tool towards more personalized treatment modalities.

High-grade serous ovarian cancer (HGSOC) is a leading cause of mortality from gynecologic malignancies worldwide. Although a transformative improvement has been shown with the introduction of PARP (poly(ADP-ribose) polymerase) inhibitors, the emergence of resistance to these drugs represents a therapeutic challenge. Hence, expanding our understanding of mechanisms behind the control of PARP1 expression can provide strategic guidance for the translation of novel therapeutic strategies. The Signal Transducer and Activator of Transcription (STAT) family of proteins consists of transcription factors critically involved in the regulation of important cellular functions. Notably, we recently demonstrated that, in cervical cancer cells, STAT1 controls PARP1 levels through multiple mechanisms, possibly involving also STAT3. Here, we tested the hypothesis that a similar mechanism might be operative in HGSOC. To this end, the impact of STAT1/STAT3 modulation on PARP1 expression was assessed in established and primary HGSOC cells, and molecular biology studies proved that STAT1 might act at both transcriptional and post-transcriptional levels to modulate the PARP1 level. Notably, bioinformatics analysis of TCGA databases demonstrated that increased STAT1 mRNA expression levels are associated with a favorable prognosis and with response to chemotherapy in HGSOC patients. Our findings suggest an alternative strategy for targeting HGSOC cells based on their dependency on PARP1.

Ovarian cancer remains a major clinical challenge with more than 40.000 annual deaths in Europe and in the United States, highlighting the need for better diagnostic and therapeutic strategies. This study first presents an immunohistochemical evaluation of the extra-domains A and B containing fibronectin (EDA-FN, EDB-FN), fibroblast activation protein (FAP), and carcinoembryonic antigen (CEA) in ovarian cancer specimens. Based on the initial results, the analysis was subsequently expanded to provide a comprehensive assessment of EDA-FN expression in human epithelial ovarian cancer tissue samples. An initial exploratory immunohistochemical analysis was performed on 60 formalin fixed paraffin embedded (FFPE) epithelial ovarian cancer (EOC) tissue sections from 47 patients, including 47 specimens collected at first diagnosis and 13 matched relapsed lesions. Tissue sections were stained using previously validated antibodies specific to EDA-FN, EDB-FN, FAP and CEA, to evaluate the stromal immunoreactive score (sIRS Part 1). Following the completion of Part 1, the study was expanded to specifically analyze the most abundant antigen found (EDA-FN) on 204 FFPE High Grade Serous ovarian cancer (HGSOC) tissue samples from 102 subjects, including primary and metastatic sites from the same patient (Part 2). In Part 1, stromal expression of EDA-FN, EDB-FN and FAP was observed in epithelial ovarian cancer with no significant differences between matched primary and relapse tumor tissues. CEA was exclusively found in mucinous ovarian cancer (MOC). EDA-FN was the most abundant antigen among the ones investigated, prompting a deeper investigation in Part 2. In the expanded EOC cohort, EDA-FN remained highly abundant across all molecular subgroups (HRp, HRd/BRCAwt, and BRCAmut) and clinical subgroups (naïve vs. pretreated patients), but was found at elevated level in metastases compared to the corresponding primary tumors. These findings highlight that EDA-FN is an excellent target for HGSOC, while CEA could serve as a potential target for MOC. Clinical investigations are warranted to evaluate innovative treatments in ovarian cancer targeting these antigens.