Explore the vast range of titles available.

Cervical cancer is the major cause of cancer related deaths in women, especially in developing countries and Human Papilloma Virus infection in conjunction with multiple deregulated signaling pathways leads to cervical carcinogenesis. TGF-β signaling in later stages of cancer is known to induce epithelial to mesenchymal transition promoting tumor growth. Phytochemicals, curcumin and emodin, are effective as chemopreventive and chemotherapeutic compounds against several cancers including cervical cancer. The main objective of this work was to study the effect of curcumin and emodin on TGF-β signaling pathway and its functional relevance to growth, migration and invasion in two cervical cancer cell lines, SiHa and HeLa. Since TGF-β and Wnt/β-catenin signaling pathways are known to cross talk having common downstream targets, we analyzed the effect of TGF-β on β-catenin (an important player in Wnt/β-catenin signaling) and also studied whether curcumin and emodin modulate them. We observed that curcumin and emodin effectively down regulate TGF-β signaling pathway by decreasing the expression of TGF-β Receptor II, P-Smad3 and Smad4, and also counterbalance the tumorigenic effects of TGF-β by inhibiting the TGF-β-induced migration and invasion. Expression of downstream effectors of TGF-β signaling pathway, cyclinD1, p21 and Pin1, was inhibited along with the down regulation of key mesenchymal markers (Snail and Slug) upon curcumin and emodin treatment. Curcumin and emodin were also found to synergistically inhibit cell population and migration in SiHa and HeLa cells. Moreover, we found that TGF-β activates Wnt/β-catenin signaling pathway in HeLa cells, and curcumin and emodin down regulate the pathway by inhibiting β-catenin. Taken together our data provide a mechanistic basis for the use of curcumin and emodin in the treatment of cervical cancer.

BackgroundSurvival rate of patients affected with anaplastic thyroid carcinoma (ATC) is less than 5% with current treatment. In ATC, BRAFV600E mutation is the major mutation that results in the transformation of normal cells in to an undifferentiated cancer cells via aberrant molecular signaling mechanisms. Although vemurufenib is a selective oral drug for the BRAFV600E mutant kinase with a response rate of nearly 50% in metastatic melanoma, our study has showed resistance to this drug in ATC. Hence the rationale of the study is to explore combinational therapeutic effect to improve the efficacy of vemurafenib along with metformin. Metformin, a diabetic drug is an AMPK activator and has recently proved to be involved in preventing or treating several types of cancer.Methods and resultsUsing iGEMDock software, a protein–ligand interaction was successful between Metformin and TSHR (receptor present in the thyroid follicular cells). Our study demonstrates that combination of vemurufenib with metformin has synergistic anti-cancer effects which was evaluated through MTT assay (cytotoxicity), colony formation assay (antiproliferation evaluation) and suppressed the progression of ATC cells growth by inducing significant apoptosis, proven by Annexin V-FITC assay (Early Apoptosis Detection). Downregulation of ERK signaling, upregulation of AMPK pathway and precision in epithelial-mesenchymal transition (EMT) pathway which were assessed by RT-PCR and Western blot provide the evidence that the combination of drugs involved in the precision of altered molecular signaling Further our results suggest that Metformin act as a demethylating agent in anaplastic thyroid cancer cells by inducing the expression of NIS and TSHR. Our study for the first time explored cAMP signaling in ATC wherein cAMP signaling is downregulated due to decrease in intracellular cAMP level upon metformin treatment.ConclusionTo conclude, our findings demonstrate novel therapeutic targets and treatment strategies for undifferentiated ATC.

The onset of colorectal cancer (CRC) is often attributed to gut bacterial dysbiosis, and thus gut microbiota are highly relevant in devising treatment strategies. Certain gut microbes, like Enterococcus spp., exhibit remarkable anti-neoplastic and probiotic properties, which can aid in silver nanoparticle (AgNPs) induced reactive oxygen species (ROS)-based CRC treatment. However, the effects of AgNPs on gut microbial metabolism have not been reported thus far. In this study, a detailed systems-level understanding of ROS metabolism in Enterococcus durans (E. durans), a representative gut microbe, was gained using constraint-based modeling, wherein, the critical association between ROS and folate metabolism was established. Experimental studies involving low AgNP concentration treatment of E. durans cultures confirmed these modeling predictions (an increased extracellular folate concentration by 52%, at the 9th h of microbial growth, was observed). Besides, the computational studies established various metabolic pathways involving amino acids, energy metabolites, nucleotides, and SCFAs as the key players in elevating folate levels on ROS exposure. The anti-cancer potential of E. durans was also studied through MTT analysis of HCT 116 cells treated with microbial culture (AgNP treated) supernatant. A decrease in cell viability by 19% implicated the role of microbial metabolites (primarily folate) in causing cell death. The genome-scale modeling approach was then extended to extensively model CRC metabolism, as well as CRC–E. durans interactions in the context of CRC treatment, using tissue-specific metabolic models of CRC and healthy colon. These findings on further validation can facilitate the development of robust and effective cancer therapy.

Reactive oxygen species (ROS) are primary effectors of cytotoxicity induced by many anti-cancer drugs. Rhythms in the pseudo-steady-state (PSS) levels of particular intracellular ROS in cancer cells and their relevance to drug effectiveness are unknown thus far. We report that the PSS levels of intracellular superoxide (SOX), an important ROS, exhibit an inherent rhythm in HCT116 colon cancer cells, which is entrained (reset) by the SOX inducer, menadione (MD). This reset was dependent on the expression of p53, and it doubled the sensitivity of the cells to MD. The period of oscillation was found to have a linear correlation with MD concentration, given by the equation, T, in h = 23.52 − 1.05 [MD concentration in µM]. Further, we developed a mathematical model to better understand the molecular mechanisms involved in rhythm reset. Biologically meaningful parameters were obtained through parameter estimation techniques; the model can predict experimental profiles of SOX, establish qualitative relations between interacting species in the system and serves as an important tool to understand the profiles of various species. The model was also able to successfully predict the rhythm reset in MD treated hepatoma cell line, HepG2.

Background: Epithelial cell adhesion molecule (EpCAM), a type I transmembrane protein of the epithelial tissues and known cell adhesion molecule, has been demonstrated to have critical role in carcinogenesis. In breast cancer, EpCAM expression has been associated with poor prognosis. The expression pattern of EpCAM across molecular subtypes of breast carcinoma has been studied in patients reporting to a South Indian multispecialty tertiary care hospital. The prognostic significance of EpCAM expression pattern and probable response to therapy has also been addressed. Materials and Methods: EpCAM expression was assessed by immunohistochemical studies on 200 breast carcinoma tissue samples of different molecular subtypes, including luminal A, luminal B, Her2Neu, and triple-negative breast cancer (TNBC). The expression was scored using the standard scoring system. A correlation was drawn with detailed clinicopathologic annotation and available outcomes data to analyze the influence of EpCAM on prognosis. Results: EpCAM expression varied significantly in the different intrinsic subtypes of breast carcinoma. Differential expression was also established with different grades of breast carcinoma with varying levels of differentiation. We observed strong EpCAM expression in TNBC among other subtypes. Conclusion: The differential expression of EpCAM among intrinsic subtypes of breast cancer and the correlation of EpCAM expression with high-grade breast carcinoma shown in the study have important implications in understanding the role of EpCAM and might form the basis for developing targeted therapies in breast cancer in the future.

Re-expression of E2 in human papillomavirus (HPV) transformed tumour cells can induce apoptosis; however, some evidences also attribute an important role to E2 in sustaining tumorigenesis. In the present paper, we studied the effects of tumour necrosis factor (TNF)-α-mediated NF-κB (nuclear factor kappa-light-chain-enhancer of activated B-cells) activation on E2-induced senescence in HPV16-integrated SiHa cells. The results show that E2 inhibits endogenous E6 gene expression and sensitizes SiHa cells to TNF-α-induced NF-κB activation. Under this condition there was an increase in the expression of senescent proteins p53, p21, p27 and p16 and senescence-associated (SA)-β-galactosidase activity indicating that TNF-α augments E2-mediated senescence. Re-expression of E2 expression with TNF-α treatment resulted in an increase in the expression of anti-apoptotic Bcl2 (B-cell lymphoma 2) protein and other pro-survival genes like cyclin D1 (cyc D1), survivin and hTERT (human telomerase reverse transcriptase). Concomitantly, E2 + TNF-α combination increased the survival of SiHa cells by positive changes in viability, proliferation and colony formation. E2-induced apoptotic tendency shifted towards senescence in presence of TNF-α by arresting the cells at both G0/G1 and G2/M phases, thus enhancing cell survival. Another observation in the present study is the significant up-regulation of key senescence messaging factors regulated by NF-κB namely interleukin (IL)-6, IL-8, high-mobility group protein A (HMGA)1 and B (HMGB)1 in E2-transfected cells treated with TNF-α. Our data provide a mechanistic basis and a new insight for the role of TNF-α and E2 in linking cellular senescence, tumorigenesis and HPV re-infection.

Background: MicroRNA-214 ( miR-214 ) has been shown to act as a tumour suppressor in human cervical and colorectal cancer cells. The aim of this study was to experimentally validate high mobility group AT-hook 1 as a novel target for miR-214- mediated suppression of growth and motility. Methods: HMGA1 and miR-214 expression levels were estimated in cervical and colorectal clinical specimens using qPCR. HMGA1 3′ untranslated region luciferase assays were performed to validate HMGA1 as a target of miR-214 . Effect of altering the expression of miR-214 or HMGA1 on proliferation, migration and invasion of human cervical and colorectal cancer cells was investigated. Results: miR-214 expression was poor while that of HMGA1 was high in cervical and colorectal cancer tissues. miR-214 -re-expression or HMGA1 downregulation inhibited proliferation, migration and invasion of cancer cells while miR-214 inhibition had opposite effects. miR-214 was demonstrated to bind to the wild-type 3′ untranslated region of HMGA1 but not with its mutant. Conclusions: Low expression of miR-214 concurrent with elevated levels of HMGA1 may contribute to cervical and colorectal cancer progression. miR-214 -mediated regulation of HMGA1 is a novel mechanism for its tumour-suppressive actions in human cervical and colorectal cancer cells and opens up avenues for novel therapeutic strategies for these two cancers.

Mutations in Smads, intermediates of transforming growth factor- β signaling, are known to contribute to the loss of sensitivity to transforming growth factor- β , a common feature of many neoplastic cells. However, not much information is available on Smad alterations in cervical cancer and so we probed, for the first time, for alterations in Smad 2 and Smad 4 genes using human cervical cancer cell lines and human cervical tissue samples. Using PCR/reverse transcription–PCR, single-stranded conformation polymorphism analysis and DNA sequencing, we observed a deletion of ‘G’ in the L3 loop (crucial in Smad–receptor interaction) in C-33A cells, and an insertion of ‘A’ in codon 122 (loss of MH2 domain) from a cervical tumor sample, both of which caused frame shift and pretermination in Smad 2 . In addition, a G/A transition at 31 bp upstream-nontranslated regions of exon 8 of Smad 4 was found in Bu 25TK cells. Smad 2 expression was less in some of the cervical tumor samples than that of nonmalignant samples and six cancer samples showed C-terminal deletions that abolish Smad 2 phosphorylation sites. The loss of expression of Smad 4 found in some cervical tumor samples was due to transcription loss rather than deletion of the gene. Our results highlight an important role for Smad 2 and Smad 4 in human cervical tumors.

Triple negative breast cancer (TNBC) is aggressive in nature, resistant to conventional therapy and often ends in organ specific metastasis. In this study, publicly available datasets were used to identify miRNA, mRNA and lncRNA hubs. Using validated mRNA-miRNA, mRNA-mRNA and lncRNA-miRNA interaction information obtained from various databases, RNA interaction networks for TNBC and its subtype specific as well as organ tropism regulated metastasis were generated. Further, miRNA-mRNA-lncRNA triad classification was performed using social network analysis from subnetworks and visualized using Cytoscape. Survival analysis of the RNA hubs, oncoprint analysis for mRNAs and pathway analysis of the lncRNAs were also performed. Results indicated that two lncRNAs (NEAT1 and CASC7) and four miRNAs (hsa-miR-106b-5p, hsa-miR-148a-3p, hsa-miR-25-3p and hsa-let-7i-5p) were common between hubs identified in TNBC and TNBC associated metastasis. The exclusive hubs for TNBC associated metastasis were hsa-miR-200b-3p, SP1, HSPA4 and RAB1B. HMGA1 was the top ranked hub in mesenchymal subtype associated lung metastasis, while hsa-miR-27a-3p was identified as the top ranked hub mRNA in luminal androgen receptor subtype associated bone metastasis. When lncRNA associated pathway analysis was performed, Hs Cytoplasmic Ribosomal Protein pathway was found to be the most significant and among the selected hubs, CTNND1, SON and hsa-miR-29c emerged as TNBC survival markers. TP53, FOXA1, MTDH and HDGF were found as the top ranked mRNAs in oncoprint analysis. The pipeline proposed for the first time in this study with validated RNA interaction data integration and graph-based learning for miRNA-mRNA-lncRNA triad classification from RNA hubs may aid experimental cost reduction and its successful execution will allow it to be extended to other diseases too. [Display omitted] •RNA hubs associated with triple negative breast cancer metastasis were identified.•mRNA-miRNA-lncRNA triad identification was performed using social network analysis.•CTNND1, SON and hsa-miR-29c emerged as TNBC survival markers.•Pipeline proposed with data integration for triad and hub identification in TNBC.•hsa-miR-27a-3p was selected as top ranked hub RNA in LAR associated bone metastasis.