Angiogenesis is an important hallmark of cancer serving a key role in tumor growth and metastasis. Therefore, tumor angiogenesis has become an attractive target for development of novel drug therapies. An increased amount of anti-angiogenic compounds is currently in preclinical and clinical development for personalized therapies. However, resistance to current angiogenesis inhibitors is emerging, indicating that there is a need to identify novel anti-angiogenic agents. In the last decade, the field of microRNA biology has exploded revealing unsuspected functions in tumor angiogenesis. These small non-coding RNAs, which have been dubbed as angiomiRs, may target regulatory molecules driving angiogenesis, such as cytokines, metalloproteinases and growth factors, including vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, epidermal growth factor, hypoxia inducible factor-1, as well as mitogen-activated protein kinase, phosphoinositide 3-kinase and transforming growth factor signaling pathways. The present review discusses the current progress towards understanding the functions of miRNAs in tumor angiogenesis regulation in diverse types of human cancer. Furthermore, the potential clinical application of angiomiRs towards anti-angiogenic tumor therapy was explored. Contents

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Vasculogenic mimicry (VM) is a mechanism whereby cancer cells form microvascular structures similar to three-dimensional channels to provide nutrients and oxygen to tumors. Unlike angiogenesis, VM is characterized by the development of new patterned three-dimensional vascular-like structures independent of endothelial cells. This phenomenon has been observed in many types of highly aggressive solid tumors. The presence of VM has also been associated with increased resistance to chemotherapy, low survival, and poor prognosis. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are non-coding RNAs that regulate gene expression at the post-transcriptional level through different pathways. In recent years, these tiny RNAs have been shown to be expressed aberrantly in different human malignancies, thus contributing to the hallmarks of cancer. In this context, miRNAs and lncRNAs can be excellent biomarkers for diagnosis, prognosis, and the prediction of response to therapy. In this review, we discuss the role that the tumor microenvironment and the epithelial-mesenchymal transition have in VM. We include an overview of the mechanisms of VM with examples of diverse types of tumors. Finally, we describe the regulation networks of lncRNAs-miRNAs and their clinical impact with the VM. Knowing the key genes that regulate and promote the development of VM in tumors with invasive, aggressive, and therapy-resistant phenotypes will facilitate the discovery of novel biomarker therapeutics against cancer as well as tools in the diagnosis and prognosis of patients.

Endometrial cancer is the fourth most frequent neoplasia for women worldwide, and over the past two decades it incidence has increased. The most common histological type of endometrial cancer is endometrioid adenocarcinoma, also known as type 1 endometrial cancer. Endometrioid endometrial cancer is associated with diverse epidemiological risk factors including estrogen use, obesity, diabetes, cigarette smoking, null parity, early menarche, and late menopause. Clinical effectiveness of chemotherapy is variable, indicating that novel molecular therapies against specific cellular processes associated to cell survival and resistance to therapy, such as autophagy, urged to ameliorate the rates of success in endometrial cancer treatment. Autophagy (also known as macroautophagy) is a specialized mechanism that maintains cell homeostasis which is activated in response to cellular stressors including nutrients deprivation, amino acids starvation, hypoxia, and metabolic stress to prolong cell survival via lysosomal degradation of cytoplasmic macromolecules and organelles. However, in human cancer cells, autophagy has a controversial function due to its dual role as self-protective or apoptotic. Conventional antitumor therapies including hormones, chemotherapy and ionizing radiation, may activate autophagy as a pro-survival tumor response contributing to treatment resistance. Intriguingly, if autophagy continues above reversibility of cell viability, autophagy can result in apoptosis of tumor cells. Here, we have reviewed the mechanisms of autophagy described in endometrial cancers, including the role of PI3K/AKT/mTOR, AMPK-mTOR, and p53 signaling pathways that trigger or inhibit the process and thus representing potential molecular targets in therapeutic clinical approaches. In addition, we discussed the recent findings indicating that autophagy can be modulated using repurposing drugs which may leads to faster experimentation and validation, as well as more easy access of the medications to patients. Finally, the promising role of dietary compounds and microRNAs in autophagy modulation is also discussed. In conclusion, although the research about autophagy is scarce but ongoing in endometrial cancer, the actual findings highlight the promising usefulness of novel molecules for directing targeted therapies.

Epithelial ovarian cancer is the fifth most frequent cause of cancer death in women. In spite of the advantages in early detection and treatment options, overall survival rates have improved only slightly in the last decades. Therefore, alternative therapeutic approaches need to overcome resistance and improve the patient survival and outcome. MicroRNAs are evolutionary conserved small non-coding RNAs that function as negative regulators of gene expression by inhibiting translation or inducing degradation of messenger RNAs. In cancer, microRNAs are aberrantly expressed thus representing potential prognostic biomarkers and novel therapeutic targets. The knowledge of novel and unexpected functions of microRNAs is rapidly evolving and the advance in the elucidation of potential clinical applications deserves attention. Recently, a specific set of microRNAs dubbed as metastamiRs have been shown to initiate invasion and metastasis in diverse types of cancer. We reviewed the current status of microRNAs in development and progression of ovarian cancer with a special emphasis on tumor cells invasion and metastasis. Also, we show an update of microRNA functions in oncogenic pathways and discuss the current scenario for potential applications in clinical and translational research in ovarian cancer.

Cancer patients who better benefit from neoadjuvant chemotherapy (NeoCh) are those who achieve a successful pathological complete response (pCR) represented by the absence of residual disease. Unfortunately, no highly sensitive and specific tumor biomarkers for predicting the clinical response to NeoCh have yet been defined. The aim of the present study was to ascertain whether miR-145-5p could discriminate between pCR and no-pCR in triple-negative breast cancer patients that received a cisplatin/doxorubicin-based neoadjuvant treatment. miR-145-5p expression was determined in breast tumors by quantitative RT-PCR. Our data showed that miR-145-5p had a significant low expression (P<0.005) in patients that achieved pCR in comparison to the non-responder group. Kaplan Meier analysis indicated that low levels of miR-145-5p were associated with increased disease-free survival. In addition, receiver operating characteristic (ROC) curve analysis suggested that miR-145-5p is a good predictor of pCR (P<0.003, AUC= 0.7899, 95% CI, 0.6382-0.9416). Quantitative RT-PCR expression analysis also revealed that miR-145-5p was downregulated in four breast cancer cell lines relative to normal cells. To study the functions of miR-145-5p, its expression was restored in triple-negative MDA-MB-231 cells and its effects in cell proliferation were evaluated by MTT assays and in apoptosis using Annexin V experiments. Data revealed that ectopic expression of miR-145-5p resulted in a significant inhibition of cell proliferation and also induced apoptosis. Moreover, miR-145-5p led to sensitization of breast cancer cells to cisplatin therapy. In addition, western blot assays indicated that miR-145-5p downregulated the TGFβR2 protein. In conclusion, miR-145-5p could be a potential biomarker of clinical response to NeoCh in triple-negative breast cancer. Functionally miR-145-5p may regulate cell proliferation, at least in part, by targeting TGFβR2.

Vasculogenic mimicry (VM) is a novel cancer hallmark in which malignant cells develop matrix-associated 3D tubular networks with a lumen under hypoxia to supply nutrients needed for tumor growth. Recent studies showed that microRNAs (miRNAs) may have a role in VM regulation. In this study, we examined the relevance of hypoxia-regulated miRNAs (hypoxamiRs) in the early stages of VM formation. Data showed that after 48 h hypoxia and 12 h incubation on matrigel SKOV3 ovarian cancer cells undergo the formation of matrix-associated intercellular connections referred hereafter as 3D channels-like structures, which arose previous to the apparition of canonical tubular structures representative of VM. Comprehensive profiling of 754 mature miRNAs at the onset of hypoxia-induced 3D channels-like structures showed that 11 hypoxamiRs were modulated (FC>1.5; p < 0.05) in SKOV3 cells (9 downregulated and 2 upregulated). Bioinformatic analysis of the set of regulated miRNAs showed that they might impact cellular pathways related with tumorigenesis. Moreover, overall survival analysis in a cohort of ovarian cancer patients ( n = 485) indicated that low miR-765, miR-193b, miR-148a and high miR-138 levels were associated with worst patients outcome. In particular, miR-765 was severely downregulated after hypoxia (FC < 32.02; p < 0.05), and predicted to target a number of protein-encoding genes involved in angiogenesis and VM. Functional assays showed that ectopic restoration of miR-765 in SKOV3 cells resulted in a significant inhibition of hypoxia-induced 3D channels-like formation that was associated with a reduced number of branch points and patterned tubular-like structures. Mechanistic studies confirmed that miR-765 decreased the levels of VEGFA, AKT1 and SRC-α transducers and exerted a negative regulation of VEGFA by specific binding to its 3‘UTR. Finally, overall survival analysis of a cohort of ovarian cancer patients ( n = 1435) indicates that high levels of VEGFA, AKT1 and SRC-α and low miR-765 expression were associated with worst patients outcome. In conclusion, here we reported a novel hypoxamiRs signature which constitutes a molecular guide for further clinical and functional studies on the early stages of VM. Our data also suggested that miR-765 coordinates the formation of 3D channels-like structures through modulation of VEGFA/AKT1/SRC-α axis in SKOV3 ovarian cancer cells.

Chemotherapy activates a novel cytoplasmic DNA damage response resulting in Golgi apparatus fragmentation and cancer cell survival. This mechanism is regulated by Golgi phosphoprotein-3 (GOLPH3)/Myo18A/F-actin axis. Analyzing the functions of miR-3135b, a small non-coding RNA with unknown functions, we found that its forced overexpression attenuates the Golgi apparatus fragmentation induced by chemotherapeutic drugs in colorectal cancer (CRC) cells. First, we found that miR-3135b is downregulated in CRC cell lines and clinical tumors. Bioinformatic predictions showed that miR-3135b could be regulating protein-encoding genes involved in cell survival, resistance to chemotherapy, and Golgi dynamics. In agreement, ectopic transfection of miR-3135b in HCT-15 cancer cells significantly inhibited cell proliferation, sensitized cells to 5-fluoruracil (5-FU), and promoted late apoptosis and necrosis. Also, miR-3135b overexpression impaired the cell cycle progression in HCT-15 and SW-480 cancer cells. Because GOLPH3, a gene involved in maintenance of Golgi structure, was predicted as a potential target of miR-3135b, we studied their functional relationships in response to DNA damage induced by chemotherapy. Immunofluorescence and cellular ultrastructure experiments using antibodies against TGN38 protein, a trans-Golgi network marker, showed that 5-FU and doxorubicin treatments result in an apoptosis-independent stacks dispersal of the Golgi ribbon structure in both HCT-15 and SW-480 cells. Remarkably, these cellular effects were dramatically hindered by transfection of miR-3135b mimics. In addition, our functional studies confirmed that miR-3135b binds to the 3′-UTR of GOLPH3 proto-oncogene, and also reduces the levels of p-AKT1 (Ser473) and p-mTOR (Ser2448) signaling transducers, which are key in cell survival and autophagy activation. Moreover, we found that after treatment with 5-FU, TGN38 factor coimmunolocalizes with beclin-1 autophagic protein in discrete structures associated with the fragmented Golgi, suggesting that the activation of pro-survival autophagy is linked to loss of Golgi integrity. These cellular effects in autophagy and Golgi dispersal were reversed by miR-3135b. In summary, we provided experimental evidence suggesting for the first time a novel role for miR-3135b in the protection of chemotherapy-induced Golgi fragmentation via GOLPH3/AKT1/mTOR axis and protective autophagy in colorectal cancer cells.