Polycystic Ovary Syndrome (PCOS), is an endocrine-metabolic disorder characterized by hyperandrogenism and ovulatory dysfunction but also obesity and hyperinsulinemia. These characteristics induce an insulin-resistant state in tissues as endometrium, affecting its reproductive functions. Myo-inositol (MYO) is an insulin-sensitizer compound used in PCOS patients; however, its insulin-sensitizer mechanism is unclear. To understand the relationship of MYO with insulin action in endometrial cells, SMIT-1 (MYO-transporter) and MYO effect on protein-levels related to insulin pathway were evaluated. SMIT-1 was assessed in endometrial tissue from women with normal-weight, obesity, insulin-resistance and PCOS; additionally, using an in-vitro model of human endometrial cells exposed to environment resembling hyperinsulinic-obese-PCOS, MYO effect was evaluated on p-AMPK and GLUT-4 levels and glucose uptake by western blot, immunocytochemistry and confocal microscopy, respectively. SMIT-1 was detected in endometrial tissue from all groups and decreased in PCOS and obesity (p<0.05 vs normal-weight). In in-vitro model, PCOS conditions decreased p-AMPK levels being restored with MYO (p<0.05). The diminished GLUT-4 protein levels promoted by PCOS environment were restored by MYO through SMIT-1 and p-AMPK-dependent mechanism (p<0.05). Also, MYO restored glucose uptake in cells under PCOS condition through a p-AMPK-dependent mechanism. Finally, these results were similar to those obtained with metformin treatment in the same in-vitro conditions. Consequently, MYO could be a potential insulin-sensitizer by its positive effects in insulin-resistant tissues as PCOS-endometrium, acting through SMIT-1, provoking AMPK activation and elevated GLUT-4 levels and consequently, increasing glucose uptake by human endometrial cells. Therefore, MYO may be used as an effective option in insulin-resistant PCOS women.

Ovarian cancer is the eighth most common cancer in women worldwide, and epithelial ovarian cancer (EOC) represents 90% of cases. Nerve growth factor (NGF) and its high affinity receptor tyrosine kinase A receptor (TRKA) have been associated with the development of several types of cancer, including EOC; both NGF and TRKA levels are elevated in this pathology. EOC presents high angiogenesis and several molecules have been reported to induce this process. NGF increases angiogenesis through its TRKA receptor on endothelial cells, and by indirectly inducing vascular endothelial growth factor expression. Other molecules controlled by NGF include ciclooxigenase-2, disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) and calreticulin (CRT), proteins involved in crucial processes needed for EOC progression. These molecules could be modified through microRNA regulation, which could be regulated by NGF. MicroRNAs are the widest family of non-coding RNAs; they bind to 3′-UTR of mRNAs to inhibit their translation, to deadenilate or to degraded them. In EOC, a deregulation in microRNA expression has been described, including alterations of miR-200 family, cluster-17-92, and miR-23b, among others. Since the NGF-microRNA relationship in pathologies has not been studied, this review proposes that some microRNAs could be associated with NGF/TRKA activation, modifying protein levels needed for EOC progression.

Nerve Growth Factor (NGF) and its high-affinity receptor tropomyosin receptor kinase A (TRKA) increase their expression during the progression of epithelial ovarian cancer (EOC), promoting cell proliferation and angiogenesis through several oncogenic proteins, such as c-MYC and vascular endothelial growth factor (VEGF). The expression of these proteins is controlled by microRNAs (miRs), such as miR-145, whose dysregulation has been related to cancer. The aims of this work were to evaluate in EOC cells whether NGF/TRKA decreases miR-145 levels, and the effect of miR-145 upregulation. The levels of miR-145-5p were assessed by qPCR in ovarian biopsies and ovarian cell lines (human ovarian surface epithelial cells (HOSE), A2780 and SKOV3) stimulated with NGF. Overexpression of miR-145 in ovarian cells was used to evaluate cell proliferation, migration, invasion, c-MYC and VEGF protein levels, as well as tumor formation and metastasis in vivo. In EOC samples, miR-145-5p levels were lower than in epithelial ovarian tumors. Overexpression of miR-145 decreased cell proliferation, migration and invasion of EOC cells, changes that were concomitant with the decrease in c-MYC and VEGF protein levels. We observed decreased tumor formation and suppressed metastasis behavior in mice injected with EOC cells that overexpressed miR-145. As expected, ovarian cell lines stimulated with NGF diminished miR-145-5p transcription and abundance. These results suggest that the tumoral effects of NGF/TRKA depend on the regulation of miR-145-5p levels in EOC cells, and that its upregulation could be used as a possible therapeutic strategy for EOC.

Alterations in bile secretion and its composition results in different pancreatobiliary alterations such as cholangiocarcinoma (CCA), gallbladder cancer (GBC) among others, which are usually detected in late stages and associated with discouraging rates of survival. Given the challenges of clinical detection of the biliary tract abnormalities, the search for biomarkers for detection, prevention and management of bile tract pathology is of the utmost importance. Current blood based biomarkers have low sensitivity and specificity; therefore, new alternatives must be identified and validated, principally in fluids that are in direct contact with the affected tissues such as bile. Molecules in contact with the site of the lesion have proven potentially diagnostic for biliary tract tumors and allow the discrimination of different pathologies and its stages. However, the acquisition of these molecules has some technical drawbacks, and poses obstacles that are hard to overcome during the implementation of these techniques in a clinical setting. Extracellular vesicles (EVs) such as exosomes have been suggested as messengers between distant cells and are representative of their tissues of origin. It has been shown that tumor derived exosomes carry nucleic acids and oncogenic proteins, that contribute to the microenvironment necessary for tumor progression. Accordingly, tumor derived exosomes have been the focus of research to identify potential screening biomarkers and therapeutic targets, since they don’t require invasive procedures and carry not only useful information but also protect their material from extracellular enzymes and contaminants, improving molecular detection. These EVs haven’t been well characterized in biliary tract cancers as its study is very recent. Nonetheless, a few studies have highlighted the role of exosomes as facilitators of these cancers’ progression. The relationship between the presence and secretion of exosomes with altered expression of different molecules with diagnostic potential has been pointed out in recent studies, both in malignant diseases and benign conditions like inflammatory abnormalities. Since biliary tract pathologies are not easily detected and are often uncovered in advanced stages, overcoming the gap between basic and clinical research to identify and validate different candidate biomarkers that are present in exosomes is a decisive goal that requires large-scale multicenter studies and standardization of isolation, purification and characterization techniques.

Caveolin-1 (CAV1) is a membrane-bound protein that suppresses tumor development yet also promotes metastasis. E-cadherin is important in CAV1-dependent tumor suppression and prevents CAV1-enhanced lung metastasis. Here, we used murine B16F10 and human A375 melanoma cells with low levels of endogenous CAV1 and E-cadherin to unravel how co-expression of E-cadherin modulates CAV1 function in vitro and in vivo in WT C57BL/6 or Rag−/− immunodeficient mice and how a pro-inflammatory environment generated by treating cells with prostaglandin E2 (PGE2) alters CAV1 function in the presence of E-cadherin. CAV1 expression augmented migration, invasion, and metastasis of melanoma cells, and these effects were abolished via transient co-expression of E-cadherin. Importantly, exposure of cells to PGE2 reverted the effects of E-cadherin expression and increased CAV1 phosphorylation on tyrosine-14 and metastasis. Moreover, PGE2 administration blocked the ability of the CAV1/E-cadherin complex to prevent tumor formation. Therefore, our results support the notion that PGE2 can override the tumor suppressor potential of the E-cadherin/CAV1 complex and that CAV1 released from the complex is phosphorylated on tyrosine-14 and promotes migration/invasion/metastasis. These observations provide direct evidence showing how a pro-inflammatory environment caused here via PGE2 administration can convert a potent tumor suppressor complex into a promoter of malignant cell behavior.