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Ovarian cancer is the most lethal gynecological malignancy due to the silent nature on its early onset and the rapid acquisition of drug resistance. Histologically heterogeneous, it includes several subtypes with different mutational landscapes, hampering the development of effective targeted therapies. Non-coding RNAs are emerging as potential new therapeutic targets in cancer. To search for a microRNA signature related to ovarian carcinomas and study its potential as effective targeted therapy, we examined the expression of 768 miRNA in a large collection of tumor samples and found miR-654-5p to be infraexpressed in ovarian serous carcinomas, the most common and aggressive type. Restoration of miR-654-5p levels reduced tumor cell viability in vitro and in vivo and impaired sphere formation capacity and viability of ovarian cancer patient-derived ascitic cells ex vivo. CDCP1 and PLAGL2 oncogenes were found to be the most relevant direct miR-654-5p targets and both genes convey in a molecular signature associated with key cancer pathways relevant to ovarian tumorigenesis, such as MYC, WNT and AKT pathways. Together, we unveiled the tumor suppressor function of miR-654-5p, suggesting that its restoration or co-targeting of CDCP1 and PLAGL2 may be an effective therapeutic approach for ovarian cancer.

El càncer d'ovari (CO) és la cinquena causa del càncer en dones i la principal causa de mort entre les malalties ginecològiques. Els símptomes inespecífics i les eines diagnòstiques actualment insuficients no detecten la malaltia en estadis inicials, quan la supervivència és del 90%. Així, al voltant del 70% dels pacients es diagnostiquen en estadis avançats, quan la supervivència és 25%. Mentre que el 80% de les pacients són inicialment quimiosensibles, el 85% d'elles desenvolupen resistència i moren per recurrència. Identificar nous biomarcadors de diagnòstic podria millorar la detecció precoç del CO. A més, desenvolupar noves estratègies terapèutiques eficients és primordial. Els micro-ARNs (miARNs) són ARN no codificants de 22nt que regulen múltiples processos silenciant ARNm diana, i s'han trobat alterats en càncer, essent possibles elements terapèutics. A més, són estables en circulació i, podrien ser eines diagnòstiques no invasives, mitjançant la saliva com a font de biomarcadors. Primer objectiu: identificar nous biomarcadors de diagnòstic per al carcinoma serós d'alt grau (HGSC). Així, 32 salives de pacients en estadis inicials i avançats de HGSC i controls van ser sotmeses a seqüenciació d'ARN. Aproximadament, es va obtenir 100 ng d'ARN per mL de saliva, amb qualitat suficient per a la seqüenciació d'ARN. Les anàlisis bioinformàtiques van mostrar al voltant del 36% de l'alineació amb el genoma humà, donant lloc a la detecció de més de 500 miARNs coneguts. L'anàlisi d'expressió diferencial va mostrar que 49 i 45 miARNs es trobàven alterats significativament en salives de les pacients amb HGSC d'estadi inicial i avançat en comparació amb els controls, respectivament. Curiosament, la família miR-34 apareix comunment alterada, amb tres membres de la família sobreexpressats en les salives de pacients amb HGSC, tant en estadis inicials com avançats, suggerint que podrien ser biomarcadors per millorar la detecció precoç de les pacients amb HGSC. Segon objectiu, Ovarian cancer (OC) is the fifth cause of cancer in women and the leading cause of death among gynecological malignancies in developed countries. The unspecific symptoms and currently insufficient diagnostic tools fail to detect the disease at an early stage, when the 5-years survival is 90%. Thus, around 70% of the patients are diagnosed at late stage, when the 5-years survival is 25%. Also, while 80% of the patients are initially chemosensitive, 85% of these develop resistance and die of recurrence. Therefore, identifying new diagnostic biomarkers would potentially improve the early detection of OC. Also, developing novel and efficient therapeutic strategies is paramount. Micro-RNAs (miRNAs) are small non-coding RNAs of 22nt that regulate multiple cellular processes by silencing of the specific target mRNAs, and have been found deregulated in cancer, being potential therapeutic elements. In addition, they are stable in circulation therefore being potential non-invasive diagnostic tools by using saliva as source of biomarkers. The first objective was to identify new miRNA diagnostic biomarkers for high-grade serous carcinoma (HGSC). Thus, 32 salivas were subjected for RNA-sequencing, in particular from early- and late-stage HGSC and control patients. Around 100 ng of RNA was found per 1 mL of saliva from control and HGSC patients, which was of sufficient quality for RNA sequencing. First bioinformatic analyses showed around 36% of alignment with the human genome, thereby resulting in a more than 500 known miRNAs and 65 De Novo miRNAs detected on average in the patients' cohort. Differential expression analysis showed that 49 and 45 miRNAs were significantly deregulated in salivas from early- and late-stage HGSC patients compared to controls, respectively. Interestingly, miR-34 family appeared commonly altered, with three members of the family overexpressed in saliva from HGSC patients, either from early and late-stages, suggesting that they could be potential bioma

In the past decade, extracellular vesicles (EVs) have been recognized as potent vehicles of intercellular communication, both in prokaryotes and eukaryotes. This is due to their capacity to transfer proteins, lipids and nucleic acids, thereby influencing various physiological and pathological functions of both recipient and parent cells. While intensive investigation has targeted the role of EVs in different pathological processes, for example, in cancer and autoimmune diseases, the EV-mediated maintenance of homeostasis and the regulation of physiological functions have remained less explored. Here, we provide a comprehensive overview of the current understanding of the physiological roles of EVs, which has been written by crowd-sourcing, drawing on the unique EV expertise of academia-based scientists, clinicians and industry based in 27 European countries, the United States and Australia. This review is intended to be of relevance to both researchers already working on EV biology and to newcomers who will encounter this universal cell biological system. Therefore, here we address the molecular contents and functions of EVs in various tissues and body fluids from cell systems to organs. We also review the physiological mechanisms of EVs in bacteria, lower eukaryotes and plants to highlight the functional uniformity of this emerging communication system.

La necessitat d'identificar nous biomarcadors que aportin una millora significativa del diagnòstic, pronòstic i del seguiment de teràpia de moltes malalties fa que avui dia la cerca de nous biomarcadors sigui un camp de la ciència increïblement explorat. Alhora, l'avenç tecnològic en el camp de la biomedicina ha fet que avui, més que mai, el nombre de nous candidats a biomarcadors hagi crescut de manera exponencial. No obstant això, en els últims anys, tot i l'elevat nombre de publicacions en aquest àmbit, només uns pocs marcadors han arribat a ser emprats en la pràctica clínica. Això es deu principalment a dues raons: els biomarcadors validats no compleixen amb les exigències de la clínica, i la fallida de molts d'aquests en la llarga i feixuga etapa de validació. El nou pipeline de cerca de biomarcadors, que afegeix etapes intermèdies en aquest procés, comporta que el percentatge d'èxit millori significativament; dit en altres paraules, que les possibilitats que aquestes noves troballes siguin incorporades a la rutina hospitalària i millorin la pràctica clínica siguin més elevades. Aquesta millora en el diagnòstic, pronòstic i seguiment de teràpia, que cada vegada més és específica del pacient que pateix la malaltia, fa que pas a pas ens trobem més a prop del que es coneix com a medicina personalitzada., Better biomarkers are urgently needed to improve diagnosis, prognosis, and targeted intherapy across a wide range of diseases. Currently, scientists are moving forward to solve this problem. New developments in research help to discover many more biomarkers than ever before. However, although the number of articles that have been published in this area is increasing, only few biomarkers have been implemented in the clinical practice. This is mainly due to two reasons: biomarkers fail to meet the demands of the clinic; and false discoveries fail during the long way that represents the validation phases. The new biomarker pipeline, which currently includes new phases in the middle of the process, has significantly increased the percentage of success. In other words, the chances that the new findings are incorporated into routine clinical practice and improve the patient care are higher than before. This improvement in diagnosis, prognosis and targeted therapy, which is increasingly more specific for each patient who suffers a certain disease, brings us step by step closer to what is known as personalized medicine.