Relevance of targeting RET/PTC junction oncogene and Wnt/β-catenin pathway in the treatment of papillary thyroid carcinoma: skill of 8-year work

Papillary thyroid carcinoma (PTC) is the most common endocrine gland malignancy and occurs frequently due to the radiation exposure. PTC is characterized by the paracentric inversion in chromosome 10 leading to the fusion of RET with several genes present in thyroid named PTC. The RET/PTCs junction oncogenes are present in around 80 % of papillary thyroid carcinoma, the most frequent ones are RET/PTC1 and RET/PTC3. Interestingly, RET/PTCs are found only in the tumour cells and not in the surrounding normal tissues, therefore, they represent a good target for RNA interference strategies. We aimed, on the one hand, to inhibit dedifferentiation due to the RET/PTC junction oncogene by siRNA and, on the other hand, to investigate a role of Wnt/β-catenin pathway in the regulation of a tissue-specific transcription factor, the thyroid transcription factor-1 (TTF-1) essential for the differentiation of the thyroid. In this paper we summarised our main results obtained during eight years that pointed a new therapeutic strategy for papillary thyroid carcinoma.Папілярний рак щитоподібної залози (PTC) є найрозповсюдже- нішим злоякісним новоутворенням ендокринних залоз, який часто спричиняється опроміненням. PTC характеризується парацентричною інверсією в хромосомі 10, яка призводить до злиття з RET декількох генів, що присутні в щитоподібній залозі саме при PTC. Злиті онкогени RET/PTCЗ знайдено майже у 80 % випадків PTC, наийчастіше зустрічаються RET/PTCЗ1 і RET/PTC3, при цьому їх не виявлено в оточуючих нормальних тканинах, внаслідок чого вони представляють собою гарну мішень для стратегій РНК-інтерференції. Мета нашої роботи полягала, з одного боку, в інгібуванні дедиференціювання з використанням міРНК злитого онкогена RET/PTC та, з іншого, – у дослідженні ролі Wnt/β-catenin шляху в регуляції тканиноспецифічного фактора транскрипції (TTF-1), важливого для диференціювання щитоподібної залози. У цій статті коротко представлено основні результати, от римані в результаті восьмирічної роботи, які вказують на нову терапевтичну стратегію для папілярного раку щитоподібної залози.Папиллярный рак щитовидной железы (PTC) является наиболее распространенным злокачественным новообразованием эндокринных желез и часто вызывается облучением. PTC характеризуется парацентрической инверсией в хромосоме 10, приводящей к слиянию с RET нескольких генов, присутствующих в щитовидной железе именнно при PTC. Слитые онкогены RET/PTC обнаружены почти в 80 % случаев PTC, наиболее часто встречаются RET/PTC1 и RET/PTC3, при этом их не выявлено в окружающих нормальных тканях, вследствие чего они представляют собой хорошую мишень для стратегий РНК-интерференции. Цель нашей работы состояла, с одной стороны, в ингибировании дедифференцирования с использованием миРНК слитого онкогена RET/PTC и, с другой, – в исследовании роли Wnt/β-catenin пути в регуляции тканеспецифического фактора транскрипции (TTF-1), важного для дифференциации щитовидной железы. В этой статье кратко представлены основные результаты, полученные в результате восьмилетней работы, указывающие на новую терапевтическую стратегию для папиллярного рака щитовидной железы

Oral manifestations of inflammatory bowel disease

Inflammatory bowel diseases (IBD), including Crohn\u2019s disease and ulcerative colitis, have important extraintestinal manifestations, notably in the oral cavity. These oral manifestations can constitute important clinical clues in the diagnosis and management of IBD, and include changes at the immune and bacterial levels. Aphthous ulcers, pyostomatitis vegetans, cobblestoning and gingivitis are important oral findings frequently observed in IBD patients. Their presentations vary considerably and might be well diagnosed and distinguished from other oral lesions. Infections, drug side effects, deficiencies in some nutrients and many other diseases involved with oral manifestations should also be taken into account. This article discusses the most recent findings on the oral manifestations of IBD with a focus on bacterial modulations and immune changes. It also includes an overview on options for management of the oral lesions of IBD

Endogenous myoglobin in human breast cancer is a hallmark of luminal cancer phenotype

BACKGROUND: We aimed to clarify the incidence and the clinicopathological value of non-muscle myoglobin (Mb) in a large cohort of non-invasive and invasive breast cancer cases. METHODS: Matched pairs of breast tissues from 10 patients plus 17 breast cell lines were screened by quantitative PCR for Mb mRNA. In addition, 917 invasive and 155 non-invasive breast cancer cases were analysed by immunohistochemistry for Mb expression and correlated to clinicopathological parameters and basal molecular characteristics including oestrogen receptor-alpha (ERalpha)/progesteron receptor (PR)/HER2, fatty acid synthase (FASN), hypoxia-inducible factor-1alpha (HIF-1alpha), HIF-2alpha, glucose transporter 1 (GLUT1) and carbonic anhydrase IX (CAIX). The spatial relationship of Mb and ERalpha or FASN was followed up by double immunofluorescence. Finally, the effects of estradiol treatment and FASN inhibition on Mb expression in breast cancer cells were analysed. RESULTS: Myoglobin mRNA was found in a subset of breast cancer cell lines; in microdissected tumours Mb transcript was markedly upregulated. In all, 71% of tumours displayed Mb protein expression in significant correlation with a positive hormone receptor status and better prognosis. In silico data mining confirmed higher Mb levels in luminal-type breast cancer. Myoglobin was also correlated to FASN, HIF-2alpha and CAIX, but not to HIF-1alpha or GLUT1, suggesting hypoxia to participate in its regulation. Double immunofluorescence showed a cellular co-expression of ERalpha or FASN and Mb. In addition, Mb levels were modulated on estradiol treatment and FASN inhibition in a cell model. CONCLUSION: We conclude that in breast cancer, Mb is co-expressed with ERalpha and co-regulated by oestrogen signalling and can be considered a hallmark of luminal breast cancer phenotype. This and its possible new role in fatty acid metabolism may have fundamental implications for our understanding of Mb in solid tumours

Global analysis of estrogen receptor beta binding to breast cancer cell genome reveals an extensive interplay with estrogen receptor alpha for target gene regulation

Background: Estrogen receptors alpha (ERa) and beta (ERb) are transcription factors (TFs) that mediate estrogen signaling and define the hormone-responsive phenotype of breast cancer (BC). The two receptors can be found co-expressed and play specific, often opposite, roles, with ERb being able to modulate the effects of ERa on gene transcription and cell proliferation. ERb is frequently lost in BC, where its presence generally correlates with a better prognosis of the disease. The identification of the genomic targets of ERb in hormone-responsive BC cells is thus a critical step to elucidate the roles of this receptor in estrogen signaling and tumor cell biology. Results: Expression of full-length ERb in hormone-responsive, ERa-positive MCF-7 cells resulted in a marked reduction in cell proliferation in response to estrogen and marked effects on the cell transcriptome. By ChIP-Seq we identified 9702 ERb and 6024 ERa binding sites in estrogen-stimulated cells, comprising sites occupied by either ERb, ERa or both ER subtypes. A search for TF binding matrices revealed that the majority of the binding sites identified comprise one or more Estrogen Response Element and the remaining show binding matrixes for other TFs known to mediate ER interaction with chromatin by tethering, including AP2, E2F and SP1. Of 921 genes differentially regulated by estrogen in ERb+ vs ERb- cells, 424 showed one or more ERb site within 10 kb. These putative primary ERb target genes control cell proliferation, death, differentiation, motility and adhesion, signal transduction and transcription, key cellular processes that might explain the biological and clinical phenotype of tumors expressing this ER subtype. ERb binding in close proximity of several miRNA genes and in the mitochondrial genome, suggests the possible involvement of this receptor in small non-coding RNA biogenesis and mitochondrial genome functions. Conclusions: Results indicate that the vast majority of the genomic targets of ERb can bind also ERa, suggesting that the overall action of ERb on the genome of hormone-responsive BC cells depends mainly on the relative concentration of both ERs in the cell

Relevance of targeting RET/PTC junction oncogene and Wnt/β-catenin pathway in the treatment of papillary thyroid carcinoma: skill of 8-year work

Papillary thyroid carcinoma (PTC) is the most common endocrine gland malignancy and occurs frequently due to the radiation exposure. PTC is characterized by the paracentric inversion in chromosome 10 leading to the fusion of RET with several genes present in thyroid named PTC. The RET/PTCs junction oncogenes are present in around 80 % of papillary thyroid carcinoma, the most frequent ones are RET/PTC1 and RET/PTC3. Interestingly, RET/PTCs are found only in the tumour cells and not in the surrounding normal tissues, therefore, they represent a good target for RNA interference strategies. We aimed, on the one hand, to inhibit dedifferentiation due to the RET/PTC junction oncogene by siRNA and, on the other hand, to investigate a role of Wnt/β-catenin pathway in the regulation of a tissue-specific transcription factor, the thyroid transcription factor-1 (TTF-1) essential for the differentiation of the thyroid. In this paper we summarised our main results obtained during eight years that pointed a new therapeutic strategy for papillary thyroid carcinoma

A NOVEL THERAPEUTIC APPROACH TO COLORECTAL CANCER IN DIABETES: ROLE OF METFORMIN AND RAPAMYCIN

The link between colorectal cancer (CRC), diabetes mellitus (DM) and inflammation is well established, and polyterapy, including rapamycin, has been adopted. This study is a novel approach that aimed at assessing the effect of a combination therapy of metformin and rapamycin on the control or prevention of CRC in diabetic animals, in presence or absence of probiotics. Fifty NOD/SCIDs male mice developed xenograft by inoculating HCT16 cells. They were equally divided into diabetics (induced by Streptozocin) and non-diabetics. Metformin was given in drinking water, whereas rapamycin was administered via intra-peritoneal injections. Probiotics were added to the double therapy two weeks before the sacrifice. Assessment was performed by clinical observation, histological analysis. Reactive oxigen species (ROS) activities and molecular analysis of Interleukin 3 and 6. Tumor Necrosis Factor alpha. AMP-activated protein Kinase and the mammalian target of rapamycin. decreases in the level of tumorigenesis resulted, to various extents, with the different treatment regimens.The combination of rapamycin and metformin had no significant result, however, after adding probiotics to the combination, there was a marked delay in tumor formation and reduction of its siza, suppression of ROS and decrease in inflammatory cytokines as well as an inhibition of phospohorylated mTOR. Existing evidence clearly supports the use of rapamycin and metformin especially in the presence of probiotics. It also highlighted the possible mechanism of action of the 2 drugs through AMPK and mTOR signaling pathways and offered preliminary data on the significant role of probiotics in the combination. Further investigation to clarify is needed

Tea catechins induce crosstalk between signaling pathways and stabilize mast cells in ulcerative colitis.

It is well documented that nutraceuticals, in general, and Green tea catechins, in particular, possess a potential therapeutic value in inflammatory bowel diseases (IBD) due to their anti-oxidative and anti-inflammatory effects. This study aimed to investigate the possible mechanism of action of catechins in a rat model of colitis induced by 2.4.6 trinitrobenzene sulfonic acid (TNBS). Thirty-five young adult Sprague-Dawley rats were divided into four groups: normal control (n=5), catechins (n=9), TNBS (n=9) and TNBS plus catechins (n=12) treated. Catechin in the form of Epigallocatechin-3-gallate (EGCG) was administered daily by intraperitoneal injection, 1 week before the induction date of UC. Biopsies of the descending colon were collected on days 3, 10 and 17, and partly frozen for molecular studies or fixed for light microscopy. The status of intestinal tissue alterations and mast cells number were also assessed, as well as the mRNA expressions of IL-6, TNF-a and NF-kB, and determination of ROS expression. Histological data depicted a significant amelioration in the TNBS- and EGCG-treated rats compared to the non-treated animals. Catechin expressed strong anti-inflammatory and anti-oxidant effects, ameliorated ulcerative colitis and stabilized mast cells. The mechanism of action occurred basically through the NF-kB pathway and possibly through a crosstalk with other pathways