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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Molecular mechanism of thyroid carcinogenesis has been well studied through the discovery of genetic abnormalities such as RET/PTC rearrangement and BRAF mutation, both of which constitutively activate MAP kinase pathway and are frequently found in papillary thyroid cancer. The TP53 mutation is thought to play a critical role in transformation of differentiated thyroid cancer into anaplastic thyroid cancer. Besides these genetic alterations, cancer stem cell theory has recently been applied to thyroid field. A better understanding of thyroid cancer stem cell may not only ameliorate our comprehension of thyroid cancer biology, but also open the possibility of innovative diagnostic procedures and development of novel targeted therapies. In this article, we mainly review thyroid carcinogenesis based on the evidence of radiation-induced cancer and cancer stem cell hypothesis.
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PMID:[Molecular mechanism of thyroid carcinogenesis]. 1801 55

This article provides an overview of the on-going molecular epidemiology studies among atomic-bomb survivors conducted at the Radiation Effects Research Foundation in Japan. The focus is on: (a) inter-individual variations in sensitivity to radiation-induced somatic mutations (glycophorin A (GPA) mutations) and their potential relevance to differences in susceptibility to radiation-related cancers and (b) the role of specific mutations/rearrangements in radiation-induced thyroid and colorectal cancers. The glycophorin A mutant fractions showed large differences between the survivors at each of the estimated bone marrow doses. Of note is the finding at doses>or=1 Gy; that the slope of the mutant fraction was significantly higher in the 'cancer group' than in the 'non-cancer group'. This study provided the basis for validating the use of gammaH2AX and reticulocyte micronucleus assays for evaluating radiosensitivity differences and genetic instability, respectively, in our studies in the coming years. Preliminary results from our molecular oncology studies on adult-onset papillary thyroid cancer provide evidence for the induction of RET/PTC rearrangements and BRAF point mutation (both known to be early stage events in adult-onset papillary thyroid cancer) but with a difference: cases associated with the rearrangements were more frequent at high doses, and developed sooner than those with BRAF mutation. In the case of colorectal cancer, the results suggest that radiation exposure might influence microsatellite instability (MSI) status through MSI-related epigenetic and genetic alterations-processes that might occur in the early stage of colorectal carcinogenesis.
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PMID:Sixty years of follow-up of Hiroshima and Nagasaki survivors: current progress in molecular epidemiology studies. 1840 59

Since the 1980s, cancer cells have been considered to be derived from well-differentiated normal cells via multiple incidents of damage to their genome, especially in oncogenes or tumor suppressor genes, which accelerate proliferation or foster malignant phenotypes, such as the ability to invade the surrounding tissue or metastasize to distant organs. In the thyroid, a novel hypothesis of carcinogenesis, the "fetal cell carcinogenesis" hypothesis, in which thyroid cancer cells are derived from the remnants of fetal cells, instead of well-differentiated somatic cells, such as thyrocytes, by de-differentiation, is proposed. In this hypothesis, thyroid cancer cells are generated from three types of fetal thyroid cells, thyroid stem cells(TSCs), thyroblasts and prothyrocytes by proliferation without differentiation, which results in anaplastic, papillary and follicular carcinoma, respectively. Genomic alternations, such as RET/PTC and PAX8-PPARgamma1 rearrangements and a mutation in the BRAF gene, play an oncogenic role by preventing thyroid fetal cells from differentiating. This hypothesis well explains the clinical and biological features and recent molecular evidence of thyroid cancer. Further, it underscores the importance of identifying stem cells and clarifying the molecular mechanism of organ development. Such data will lead to better understanding of thyroid carcinogenesis and the establishment of more accurate diagnostic methods and more effective therapies. Analysis of molecular behavior in a single tumor cell will be a key technology in the future clinical pathology. Fetal cell science may be the leading research theme in the next few decades.
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PMID:[Fetal cell carcinogenesis hypothesis and its impact on clinical pathology of cancer]. 1854 90

A major early event in papillary thyroid carcinogenesis is constitutive activation of the mitogen-activated protein kinase signaling pathway caused by alterations of a single gene, typically rearrangements of the RET and NTRK1 genes or point mutations in the BRAF and RAS genes. In childhood papillary thyroid cancer, regardless of history of radiation exposure, RET/PTC rearrangements are a major event. Conversely, in adult-onset papillary thyroid cancer among the general population, the most common molecular event is BRAF(V600E) point mutation, not RET/PTC rearrangements. To clarify which gene alteration, chromosome aberration, or point mutation preferentially occurs in radiation-associated adult-onset papillary thyroid cancer, we have performed molecular analyses on RET/PTC rearrangements and BRAF(V600E) mutation in 71 papillary thyroid cancer cases among atomic bomb survivors (including 21 cases not exposed to atomic bomb radiation), in relation to radiation dose as well as time elapsed since atomic bomb radiation exposure. RET/PTC rearrangements showed significantly increased frequency with increased radiation dose (P(trend) = 0.002). In contrast, BRAF(V600E) mutation was less frequent in cases exposed to higher radiation dose (P(trend) < 0.001). Papillary thyroid cancer subjects harboring RET/PTC rearrangements developed this cancer earlier than did cases with BRAF(V600E) mutation (P = 0.03). These findings were confirmed by multivariate logistic regression analysis. These results suggest that RET/PTC rearrangements play an important role in radiation-associated thyroid carcinogenesis.
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PMID:RET/PTC rearrangements preferentially occurred in papillary thyroid cancer among atomic bomb survivors exposed to high radiation dose. 1875 33

In human papillary thyroid carcinomas (PTCs), the genetic alterations of RET/PTC, RAS or BRAF account for about 60-70% of cases with practically no overlap, providing strong genetic evidence that constitutive active signaling along MAPK pathway is critical for PTC development. In the remaining 30-40% of the cases, the oncogenes are still unknown. RAP1 is a member of the RAS family of small G proteins transmitting signals from the TSH-R to MAPK pathway using cAMP-dependent mechanism in thyroid cells. RAP1 was shown to have both mitogenic and tumorigenic properties in certain systems; however, the potential role of RAP1 mutation in thyroid carcinogenesis has yet to be elucidated. In this study, we analyzed the mutational status of RAP1 gene in 36 Russian patients with PTCs without RET/PTC rearrangement, BRAF mutation or RAS mutation. No mutations in either RAP1A or RAP1B genes were found. These results suggest that RAP1 mutation does not play an important role in PTC pathogenesis.
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PMID:Mutation analysis of RAP1 gene in papillary thyroid carcinomas. 1894 74

Exposure to ionizing radiation is a well-known risk factor for a number of human cancers, including leukemia and thyroid cancer. It has been known for a long time that exposure of cells to radiation results in extensive DNA damage; however, a small number of studies have tried to explain the mechanisms of radiation-induced carcinogenesis. The high prevalence of RET/PTC rearrangements in patients who have received external radiation, and the evidence of in vitro induction of RET rearrangements in human cells, suggest an enhanced sensitivity of the RET genomic region to damage by ionizing radiation. To assess whether RET is indeed more sensitive to radiations than other genomic regions, we used a COMET assay coupled with fluorescence in situ hybridization, which allows the measurement of DNA fragmentation in defined genomic regions of single cells. We compared the initial DNA damage of the genomic regions of RET, CXCL12/SDF1, ABL, MYC, PLA2G2A, p53, and JAK2 induced by ionizing radiation in both a lymphoblastoid and a fetal thyroid cell line. In both cell lines, RET fragmentation was significantly higher than in other genomic regions. Moreover, a differential distribution of signals within the COMET was associated with a higher percentage of RET fragments in the tail. RET was more susceptible to fragmentation in the thyroid-derived cells than in lymphoblasts. This enhanced susceptibility of RET to ionizing radiation suggests the possibility of using it as a radiation exposure marker.
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PMID:Enhanced sensitivity of the RET proto-oncogene to ionizing radiation in vitro. 1897 43

RET finger protein (RFP), which belongs to the large B-box RING finger protein family, has been reported to be expressed in breast carcinoma cell lines. We conducted this study to evaluate the expression level of RFP in breast carcinomas. Tissue microarrays were constructed from 133 cases of invasive breast carcinoma. Sections obtained from tissue arrays and whole sections from 10 non-neoplastic breast tissues were stained for ER, PR, ErbB2, and RFP using immunohistochemistry, and ErbB2 gene status was evaluated by FISH. The correlation between various immunohistochemical markers was determined. We found nuclear RFP expression in 41.4% of invasive carcinomas and in none of the non-neoplastic breast tissues. We also stained whole sections of 29 cases of invasive breast carcinoma, which included the TMA study, and 10 cases of ductal carcinoma in situ (DCIS) by RFP. We observed that four (40%) of the DCIS cases were positive with RFP. In statistical analysis, there was a significant, positive association between RFP and ErbB2 status at the protein level (p=0.002) and the gene level (p=0.049). There was no statistically significant association between the expression of RFP and tumor size, LN status, ER, PR, and grade (p>0.05). However, we found a significant association between age and RFP expression. RFP expression was stronger in patients 50 years or older (p=0.048). In our study, the expression of RFP correlated strongly with ErbB2 status. Our study is the first in the literature to show expression of RFP in patients with breast carcinoma. However, the possible role of RFP in breast carcinogenesis needs to be investigated in more detailed clinical and experimental studies.
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PMID:RET finger protein expression in invasive breast carcinoma: relationship between RFP and ErbB2 expression. 1923 40

Histone deacetylases (HDAC) are involved in carcinogenesis through their regulation of cell proliferation, differentiation, and survival. The inhibitors of HDAC exhibit profound synergistic effects in cancer treatment when combined with other anticancer drugs. However, the molecular mechanisms underlying this synergy are not fully understood. Here, we show that HDAC1 increases the resistance of cancer cells to oxidative stress by negatively regulating the expression of thioredoxin binding protein 2 (TBP-2). We found that the recruitment of HDAC1 to the TBP-2 promoter is mediated by a protein complex consisting of RET finger protein (RFP; also called TRIM27) and the trimeric transcription factor NF-Y. Accordingly, RNA interference-mediated depletion of RFP led to the disruption of the protein complex and a marked increase in the sensitivity of cancer cells to cisplatin, a potent inducer of oxidative stress. Furthermore, high levels of RFP expression correlated with down-regulation of TBP-2 in human colon cancers and were associated with poor clinical outcome. These findings reveal the diverse cancer-promoting activities of HDAC1 and identify RFP as a key regulator that provides cancer cells with resistance to anticancer drugs.
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PMID:Characterization of the HDAC1 complex that regulates the sensitivity of cancer cells to oxidative stress. 1935 25

Tenascin C (Tn-C) is an extracellular matrix glycoprotein that is expressed early in carcinogenesis including intraepithelial neoplastic lesions of different organs. In this study, we analyze whether stroma reaction seen by Tn-C expression is detected early in tumorigenesis of medullary thyroid carcinoma (MTC) including medullary microcarcinoma and C-cell hyperplasia (CCH), which is accepted to be a precursor lesion of MTC in the setting of RET oncogene germ-line mutation. Tn-C was expressed in the stroma of all medullary microcarcinoma and in the stroma next to CCH. Stromal Tn-C expression was significantly more often seen in CCH with concomitant MTC than in isolated CCH of hereditary as well as nonhereditary cases (p = 0.001 and p = 0.016, respectively). We conclude that Tn-C expression and thus early stroma remodeling is seen in medullary microcarcinoma and CCH. Stromal Tn-C expression seems to be an indicator of a further step in carcinogenesis of MTC irrespective of a RET oncogene germ-line mutation.
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PMID:Tenascin C in medullary thyroid microcarcinoma and C-cell hyperplasia. 1948 61

Differentiated thyroid cancers are the predominant malignancies of the thyroid. Due to advances in the understanding of the activation of the cell proliferation pathway at a molecular level, multiple genetic alterations have been linked to the development of thyroid carcinogenesis. Although the genetic alterations can be categorized into 7 categories, the BRAF mutation, RET/PTC, Pax8/PPARGamma, and dysfunctional Fas pathway have been most commonly described. Each of the gene alterations can ultimately result in cancer development, invasion and/or metastasis. This article provides a detailed review of the altered cell proliferation pathway activations found in thyroid carcinogenesis. The molecular targets that may be disrupted by therapeutic agents during the abnormal proliferation are also summarized.
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PMID:Genetic alterations in differentiated thyroid cancers. 1959 19


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