Diacylglycerol lipase alpha promotes tumorigenesis in oral cancer by cell-cycle progression.

Diacylglycerol lipase alpha (DAGLA), which catalyzes the hydrolysis of diacylglycerol to 2-arachidonoylglycerol and free fatty acid, is required for axonal growth during the brain development and for retrograde synaptic signaling at mature synapses. So far, no information was found regarding the possible role of DAGLA in human tumorigenesis. Thus, the current study sought to clarify the contribution of DAGLA in oral squamous cell carcinomas (OSCCs) and assess the clinical possibilities for OSCC treatment. Using real-time quantitative reverse transcription-polymerase chain reaction, immunoblotting, and immunohistochemistry, we found a significant up-regulation of DAGLA in OSCCs compared with normal cells and tissues both at mRNA and protein expression levels. Knockdown models in OSCC-derived cell lines for DAGLA (siDAGLA) and treatment with a lipase inhibitor (orlistat) showed several depressed cellular functions, including cellular proliferation and migratory activities through cell-cycle arrest at G1 phase. Furthermore, we found that DAGLA-positive OSCC samples were correlated highly with the primary tumoral size. We concluded that DAGLA may be a key determinant in tumoral progression and might be a therapeutic target for OSCCs.

Cavin-2 in oral cancer: A potential predictor for tumor progression.

Cavin-2 (CVN2) affects formation of large caveolae, which are membrane-rich cholesterol domains associated with several functions in signal transduction. Accumulating evidence suggests that CVN2 is present in many cellular types; however, the molecular mechanisms of CVN2 in cancers and its clinical relevance are unknown. We proposed a mechanism by which CVN2 regulates caveolin-1 expression leading to slow cellular proliferation by inactivation of the extracellular regulated kinase (ERK) pathway. Quantitative reverse transcriptase-polymerase chain reaction and immunoblot analyses were used to assess the CVN2 regulation mechanism in oral squamous cell carcinoma (OSCC). Immunohistochemistry (IHC) was performed to analyze the correlation between CVN2 expression and clinical behavior in 115 patients with OSCC. A CVN2 overexpressed model of OSCC cells (oeCVN2 cells) was used for functional experiments. CVN2 expression was down-regulated significantly (P < 0.05) in OSCCs compared with normal counterparts in vitro and in vivo. In addition to the findings that a serum deprivation culture induced up-regulation of CVN2 and slowed cellular proliferation, oeCVN2 cell growth decreased because of cell-cycle arrest at the G1 phase resulting from up-regulated cyclin-dependent kinase inhibitors (p21(Cip1) and p27(Kip1) ) and down-regulated cyclins (cyclin D1, cyclin E) and cyclin-dependent kinases (CDK2, CDK4, and CDK6). Interestingly, CVN2 overexpression facilitated caveolin-1 recruitment and colocalization with each other. We also found decreased ERK phosphorylation levels, an upstream event in cell-cycle arrest. Clinically, IHC data from primary OSCCs showed high tumoral progression in CVN2-negative patients with OSCC. CVN2 may be a possible key regulator of OSCC progression via the CVN2/caveolin-1/ERK pathway and a potential therapeutic target for developing new treatments for OSCCs. © 2015 Wiley Periodicals, Inc.

Cancer-associated fibroblasts in gynecological malignancies: are they really allies of the enemy?

Molecular and cellular components of the tumor microenvironment are essential for cancer progression. The cellular element comprises cancer cells and heterogeneous populations of non-cancer cells that satisfy tumor needs. Immune, vascular, and mesenchymal cells provide the necessary factors to feed the tumor mass, promote its development, and favor the spread of cancer cells from the primary site to adjacent and distant anatomical sites. Cancer-associated fibroblasts (CAFs) are mesenchymal cells that promote carcinogenesis and progression of various malignant neoplasms. CAFs act through the secretion of metalloproteinases, growth factors, cytokines, mitochondrial DNA, and non-coding RNAs, among other molecules. Over the last few years, the evidence on the leading role of CAFs in gynecological cancers has notably increased, placing them as the cornerstone of neoplastic processes. In this review, the recently reported findings regarding the promoting role that CAFs play in gynecological cancers, their potential use as therapeutic targets, and the new evidence suggesting that they could act as tumor suppressors are analyzed and discussed.

In vitro and in vivo antitumor activity of Yerba Mate extract in colon cancer models.

Yerba Mate (Ilex paraguariensis St. Hill. Aquifoliaceae) is a native South American tree and has a large amount of bioactive compounds. Colorectal cancer (CRC) is one of the so-called westernized diseases and is the third most common cancer in both men and women. Efficient strategies for the treatment of CRC are extensively being explored including dietary intervention. The objective of our research was to evaluate the effects of Yerba Mate extract on cell proliferation, invasive capacity of tumor cells, and angiogenesis. For this, in vitro and in vivo experimentation was carried out using CRC models. The extract was generated by aqueous extraction and prepared according to traditional American procedure of preparing mate infusion. In vitro results showed that the Yerba Mate extract inhibits CT26 and COLO 205 cell proliferation with IC50 values of 0.25 and 0.46 mg/mL, respectively. We demonstrated by TUNEL assay that one of the mechanisms by which Yerba Mate extract decreases cell proliferation is by induction of apoptosis. In a murine syngeneic tumor model, oral administration of Yerba Mate extract in a dose of 1.6 g/kg/day significantly inhibited angiogenesis and tumor growth without affecting biological parameters or body weight. Our findings suggest that Yerba Mate may be a promising agent for the treatment of colon cancer and could be used as an herbal medicine or functional food ingredient. PRACTICAL APPLICATION: Considering the chemical composition and presence of phenolic compounds with their free-radical scavenging activities and bioactivities against colon cancer cells, Yerba Mate can be a promising candidate as healthy food sources in human nutrition, and also be considered a natural source of potential antitumor agents. Taking into account the economic importance of Yerba Mate in Argentina, this vegetable would have a greater commercial value as a functional food.

Enhancement of Breast Cancer Cell Aggressiveness by lncRNA H19 and its Mir-675 Derivative: Insight into Shared and Different Actions.

Breast cancer is a major public health problem and the leading world cause of women death by cancer. Both the recurrence and mortality of breast cancer are mainly caused by the formation of metastasis. The long non-coding RNA H19, the precursor of miR-675, is involved in breast cancer development. The aim of this work was to determine the implication but, also, the relative contribution of H19 and miR-675 to the enhancement of breast cancer metastatic potential. We showed that both H19 and miR-675 increase the invasive capacities of breast cancer cells in xenografted transgenic zebrafish models. In vitro, H19 and miR-675 enhance the cell migration and invasion, as well as colony formation. H19 seems to induce the epithelial-to-mesenchymal transition (EMT), with a decreased expression of epithelial markers and an increased expression of mesenchymal markers. Interestingly, miR-675 simultaneously increases the expression of both epithelial and mesenchymal markers, suggesting the induction of a hybrid phenotype or mesenchymal-to-epithelial transition (MET). Finally, we demonstrated for the first time that miR-675, like its precursor H19, increases the stemness properties of breast cancer cells. Altogether, our data suggest that H19 and miR-675 could enhance the aggressiveness of breast cancer cells through both common and different mechanisms.

Imunoexpressão de ciclooxigenase-2 (COX-2) e caderina-e no câncer gástrico [Manuscrito]: contribuição ao estudo da progressão tumoral-linfonodal / Immunostaining of cyclooxygenase-2 (COX-2) and E-cadherin and gastric cancer [manuscript]: contribution to the study of lymph node tumor-progression

COX-2 e Caderina-E participam de forma fundamental na manutenção do estado fisiológico da mucosa gástrica e têm papel essencial na reação inflamatória e reparo, e no câncer. O objetivo deste trabalho é avaliar a expressão das duas proteínas no carcinoma gástrico e metástases linfonodais e suas possíveis participações na progressão tumoral. Foram utilizados 97 casos de gastrectomias por carcinoma gástrico, 36 dos quais com linfonodos disponíveis, dos arquivos do Hospital do Câncer do Ceará. Os casos foram classificados nos tipos intestinal (40 casos), difuso (34), mistos (16) e não-classificados (7 casos) de acordo com a classificação de Lauren (1965). Utilizou-se técnica de tissue microarray associada à imunohistoquímica com anticorpo monoclonal anti-COX-2 e anti-Caderina-E e sistema de detecção universal estreptavidina-biotina-peroxidase. A expressão de COX-2 foi avaliada de acordo com os seguintes escores: Intensidade (I): 0=negativa; 1=discreta; 2=moderada; 3=acentuada; Extensão (E) de células coradas: 1=0 a 25%; 2= >25 a 50%; 3= >50 a 75%; 4= >75 a 100%. Escore final: I x E, sendo considerados escores < 6 como COX-2 de baixa expressão e escores >= 6 de alta expressão...