Identification of three novel proteins (SGSM1, 2, 3) which modulate small G protein (RAP and RAB)-mediated signaling pathway

We report a novel protein family consisting of three members, each of which contains RUN and TBC motifs and appears to be associated with small G protein-mediated signal transduction pathway. We named these proteins as small G protein signaling modulators (SGSM1/2/3). Northern blot analysis revealed that human SGSM2/3 are expressed ubiquitously in various tissues, whereas SGSM1 is expressed mainly in brain, heart, and testis. Mouse possessed the same protein family genes, and the in situ hybridization and immunohistochemical staining of tissue sections revealed that mouse Sgsm1/2/3 are expressed in the neurons of central nervous system, indicating the strong association of Sgsm family with neuronal function. Furthermore, endogenous Sgsm1 protein was localized in the trans-Golgi network of mouse Neuro2a cells by immunofluorescence microscopy. Expression of various cDNA constructs followed by immunoprecipitation assay revealed that human SGSM1/2/3 proteins are coprecipitated with RAP and RAB subfamily members of the small G protein superfamily. Based on these results, we postulated that the SGSM family members function as modulators of the small G protein RAP and RAB-mediated neuronal signal transduction and vesicular transportation pathways.     

miR-206 inhibits thyroid cancer proliferation and invasion by targeting RAP1B

Thyroid cancer (TC) is one of the primary tumors arisen from endocrine system. The purpose of this study was to investigate the underlying mechanism by which RAP1B (Ras-related protein Rap-1b) modulates microRNA (miR)-206 related effects on TC cells. Expression of miR-206 and RAP1B was analyzed in cells and tissues. miR-206 mimics or inhibitors and RAP1B vector were used in functional experiments to investigate the effects of miR-206 and RAP1B on cell activities including proliferation, migration, and invasion. Luciferase assay was performed to explore the association between miR-206 and RAP1B. The influence of miR-206 on tumorigenesis of TC cells was investigated using an ex vivo model. Our results demonstrated the reduce of miR-206 in TC tissues and cell lines in which RAP1B was increased. Overexpression of miR-206 significantly inhibited the functional capacities of TPC-1 cells including proliferation, invasion, and migration, most likely, through reducing the expression of RAP1B. Xenograft experiment showed that increased miR-206 could effectively inhibit the tumorigenesis of TC cells. Our study showed that miR-206 negatively regulated cell activities of proliferation, invasion, and migration in TC via suppressing RAP1B expression, suggesting that miR-206 exerts a vital role in TC.     

Small G protein signalling modulator 2 (SGSM2) is involved in oestrogen receptor-positive breast cancer metastasis through enhancement of migratory cell adhesion via interaction with E-cadherin

The function of small G protein signalling modulators (SGSM1/2/3) in cancer remains unknown. Our findings demonstrated that SGSM2 is a plasma membrane protein that strongly interacted with E-cadherin/β-catenin. SGSM2 downregulation enhanced the phosphorylation of focal adhesion kinase (FAK; Y576/577), decreased the expression of epithelial markers such as E-cadherin, β-catenin, and Paxillin, and increased the expression of Snail and Twist-1, which reduced cell adhesion and promoted cancer cell migration. Oestrogen and fibronectin treatment was found to promote the colocalization of SGSM2 at the leading edge with phospho-FAK (Y397). The BioGRID database showed that SGSM2 potentially interacts with cytoskeleton remodelling and cell-cell junction proteins. These evidences suggest that SGSM2 plays a role in modulating cell adhesion and cytoskeleton dynamics during cancer migration.     

Genome-wide expression analysis suggests a crucial role of dysregulation of matrix metalloproteinases pathway in undifferentiated thyroid carcinoma

Background

Thyroid cancer (TC) is the most common malignant cancer of the Endocrine System. Histologically, there are three main subtypes of TC: follicular, papillary and anaplastic. Diagnosing a thyroid tumor subtype with a high level of accuracy and confidence is still a difficult task because genetic, molecular and cellular mechanisms underlying the transition from differentiated to undifferentiated thyroid tumors are not well understood.A genome-wide analysis of these three subtypes of thyroid carcinoma was carried out in order to identify significant differences in expression levels as well as enriched pathways for non-shared molecular and cellular features between subtypes.

Results

Inhibition of matrix metalloproteinases pathway is a major event involved in thyroid cancer progression and its dysregulation may result crucial for invasiveness, migration and metastasis. This pathway is drastically altered in ATC while in FTC and PTC, the most important pathways are related to DNA-repair activation or cell to cell signaling events.

Conclusion

A progression from FTC to PTC and then to ATC was detected and validated on two independent datasets. Moreover, PTX3, COLEC12 and PDGFRA genes were found as possible candidates for biomarkers of ATC while GPR110 could be tested to distinguish PTC over other tumor subtypes. The genome-wide analysis emphasizes the preponderance of pathway-dysregulation mechanisms over simple gene-malfunction as the main mechanism involved in the development of a cancer phenotype.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1372-0) contains supplementary material, which is available to authorized users.     

The function of SNHG7/miR-449a/ACSL1 axis in thyroid cancer

Thyroid cancer (TC) has been characterized as the most common malignant malady of the endocrine system. Small nucleolar RNA host gene 7 (SNHG7) has been reported to serve as a key regulator in a large number of human cancer types, but its role in TC and the underlying regulatory mechanism have never been evaluated yet. The present study indicated that the expression of SNHG7 was markedly higher in TC cell lines. Knockdown of SNHG7 led to a suppression of TC cell progression and migration. Acyl-CoA synthetase long-chain family member 1 (ACSL1) has also been demonstrated as an oncogene in many cancers. Herein an inhibition of ACSL1 after SNHG7 knockdown was captured. Further, the suppressing effects of SNHG7 knockdown on TC cell processes were counteracted by ACSL1 overexpression. Data from online bioinformatics analysis, RNA immunoprecipitation, and luciferase reporter assays validated the interaction between microRNA-449a (miR-449a) and SNHG7 or ACSL1. It was also verified that SNHG7 sequestered miR-449a and therefore elevated ACSL1 expression levels. To conclude, the current study indicated that SNHG7 promoted proliferation and migration of TC cells by sponging miR-449a and therefore upregulating ACSL1. The present study may provide more explorations about the molecular regulation mechanism of long noncoding RNAs in TC progression.     

TGF-β, to target or not to target; to prevent thyroid cancer progression?

Thyroid cancer (TC) is a common endocrine cancer with a rising incidence. Current treatment fails to eliminate aggressive thyroid tumours, prompting an investigation into the processes that cause disease progression. In this review, we provide insight into TGF-β driven epithelial to mesenchymal transition (EMT), summarizing the current literature surrounding thyroid carcinogenesis, and discuss the potential for therapeutic strategies targeting the TGF-β signalling pathway. Understanding the underlying mechanisms that regulate cancer stem cell (CSC) growth and TGF-β signalling may provide novel therapeutic approaches for highly resistant TCs.     

Effects of mutant Ran/TC4 proteins on cell cycle progression.

Ran/TC4, a member of the RAS gene superfamily, encodes an abundant nuclear protein that binds and hydrolyzes GTP. Transient expression of a Ran/TC4 mutant protein deficient in GTP hydrolysis blocked DNA replication, suggesting a role for Ran/TC4 in the regulation of cell cycle progression. To test this possibility, we exploited an efficient transfection system, involving the introduction of cDNAs in the pMT2 vector into 293/Tag cells, to analyze phenotypes associated with mutant and wild-type Ran/TC4 expression. Expression of a Ran/TC4 mutant protein deficient in GTP hydrolysis inhibited proliferation of transfected cells by arresting them predominantly in the G2, but also in the G1, phase of the cell cycle. Deletion of an acidic carboxy-terminal hexapeptide from the Ran/TC4 mutant did not alter its nuclear localization but did block its inhibitory effect on cell cycle progression. These data suggest that normal progression of the cell cycle is coupled to the operation of a Ran/TC4 GTPase cycle. Mediators of this coupling are likely to include the nuclear regulator of chromosome condensation 1 protein and the mitosis-promoting factor complex.     

Molecular Pathways Associated with Aggressiveness of Papillary Thyroid Cancer

The most common thyroid malignancy is papillary thyroid cancer (PTC). Mortality rates from PTC mainly depend on its aggressiveness. Geno- and phenotyping of aggressive PTC has advanced our understanding of treatment failures and of potential future therapies. Unraveling molecular signaling pathways of PTC including its aggressive forms will hopefully pave the road to reduce mortality but also morbidity from this cancer. The mitogen-activated protein kinase and the phosphatidylinositol 3-kinase signaling pathway as well as the family of RAS oncogenes and BRAF as a member of the RAF protein family and the aberrant expression of microRNAs miR-221, miR-222, and miR-146b all play major roles in tumor initiation and progression of aggressive PTC. Small molecule tyrosine kinase inhibitors targeting BRAF-mediated events, vascular endothelial growth factor receptors, RET/PTC rearrangements, and other molecular targets, show promising results to improve treatment of radioiodine resistant, recurrent, and aggressive PTC.     

PCNP is a novel regulator of proliferation,migration, and invasion in human thyroid cancer

Thyroid cancer (TC) has increased globally, with a prominent increase in small, papillary thyroid cancers. PEST-containing nuclear protein (PCNP), a nuclear protein, has been found to be associated with human cancers in recent years. However, the role and molecular mechanism of PCNP in thyroid cancer remain underexplored. In the present study, the results showed that the expression levels of PCNP in human thyroid tissues were higher than those in adjacent non‐tumor tissues. Overexpression of PCNP reduced the proliferation, migration, and invasion of human thyroid cancer cells and down‐regulation of PCNP showed reverse effects. In addition, PCNP regulated cell cycle arrest through modifications in the expression of cell cycle regulating genes and PCNP affected apoptosis via activation of ERK/JNK/p38 pathway in thyroid cancer cells. Moreover, PCNP overexpression promoted autophagy by reducing the expression levels of Wnt/β‐catenin pathway in TC cells, however, PCNP knockdown had opposite effects. Furthermore, PCNP overexpression reduced the growth of xenografted human thyroid cancer, whereas PCNP knockdown showed opposite trends. In conclusion, in vitro and in vivo data demonstrate that PCNP as a tumor suppressor gene may serve as a novel prognostic and potential therapeutic marker in human thyroid cancer.     

Degradation of human RAP80 is cell cycle regulated by Cdc20 and Cdh1 ubiquitin ligases

Receptor-associated protein 80 (RAP80) is a component of the BRCA1-A complex that recruits BRCA1 to DNA damage sites in the DNA damage-induced ubiquitin signaling pathway. RAP80-depleted cells showed defective G(2)-M phase checkpoint control. In this study, we show that RAP80 protein levels fluctuate during the cell cycle. Its expression level peaked in the G(2) phase and declined during mitosis and progression into the G(1) phase. Also, RAP80 is polyubiquitinated and degraded by the anaphase-promoting complex (APC/C)(Cdc20) or (APC/C)(Cdh1). Consistent with this, knockdown of Cdc20 or Cdh1 expression by transfecting with small interfering RNAs blocked RAP80 degradation during mitosis or the G(1) phase, respectively. A conserved destruction box (D box) in RAP80 affected its stability and ubiquitination, which was dependent on APC/cyclosome(Cdc20) (C(Cdc20)) or APC/cyclosome(Cdh1) (C(Cdh1)). In addition, overexpression of RAP80 destruction box1 deletion mutant attenuated mitotic progression. Thus, APC/C(Cdc20) or APC/C(Cdh1) complexes regulate RAP80 stability during mitosis to the G(1) phase, and these events are critical for a novel function of RAP80 in mitotic progression.     

Oncogenic RAS induces accelerated transition through G2/M and promotes defects in the G2 DNA damage and mitotic spindle checkpoints

Activating mutations of RAS are prevalent in thyroid follicular neoplasms, which commonly have chromosomal losses and gains. In thyroid cells, acute expression of HRAS(V12) increases the frequency of chromosomal abnormalities within one or two cell cycles, suggesting that RAS oncoproteins may interfere with cell cycle checkpoints required for maintenance of a stable genome. To explore this, PCCL3 thyroid cells with conditional expression of HRAS(V12) or HRAS(V12) effector mutants were presynchronized at the G(1)/S boundary, followed by activation of expression of RAS mutants and release from the cell cycle block. Expression of HRAS(V12) accelerated the G(2)/M phase by approximately 4 h and promoted bypass of the G(2) DNA damage and mitotic spindle checkpoints. Accelerated passage through G(2)/M and bypass of the G(2) DNA damage checkpoint, but not bypass of the mitotic spindle checkpoint, required activation of mitogen-activated protein kinase (MAPK). However, selective activation of the MAPK pathway was not sufficient to disrupt the G(2) DNA damage checkpoint, because cells arrested appropriately in G(2) despite conditional expression of HRAS(V12,S35) or BRAF(V600E). By contrast to the MAPK requirement for radiation-induced G(2) arrest, RAS-induced bypass of the mitotic spindle checkpoint was not prevented by pretreatment with MEK inhibitors. These data support a direct role for the MAPK pathway in control of G(2) progression and regulation of the G(2) DNA damage checkpoint. We propose that oncogenic RAS activation may predispose cells to genomic instability through both MAPK-dependent and independent pathways that affect critical checkpoints in G(2)/M.     

IncRNA MAPKAPK5-AS1 promotes proliferation and migration of thyroid cancer cell lines by targeting miR-519e-5p/YWHAH

Thyroid cancer is a common malignant tumour of the endocrine system and ranks ninth in cancer incidence worldwide. An extensive body of evidence has demonstrated that lncRNAs play a critical role in the progression of thyroid cancer. The lncRNA MAPKAPK5-AS1 has been reported to be abnormally expressed and to play a role in the development of various human cancers. However, MAPKAPK5-AS1’s potential role in thyroid cancer progression remains unknown. The objective of our study was to explore the role and mechanism of MAPKAPK5-AS1 in thyroid cancer cells and provide a potential target for its biological diagnosis and treatment. We transfected sh-MAPKAPK5-AS1 and sh-NC into BCPAP and TPC-1 cells for loss-of-function assays. Results of RT-qPCR analysis demonstrated that MAPKAPK5-AS1 was more highly expressed in thyroid cancer cells compared to normal cells. Functional assays demonstrated that interfering with the expression of MAPKAPK5-AS1 notably repressed proliferation and invasion and accelerated apoptosis of BCPAP and TPC-1 cells. Mechanistically, we found that miR-519e-5p was negatively regulated by MAPKAPK5-AS1 and that tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein eta (YWHAH) was a target of miR-519e-5p. Additionally, rescue assays demonstrated that downregulation of MAPKAPK5-AS1 expression inhibited cell proliferation, migration, and invasion and promoted apoptosis by sponging miR-519e-5p, thereby increasing YWHAH expression. Ultimately, our study revealed that MAPKAPK5-AS1 promotes proliferation and migration of thyroid cancer cells by targeting the miR-519e-5p/YWHAH axis, which provides novel insight into the development and progression of thyroid cancer.Key words: IncRNA MAPKAPK5-AS1, MiR-519e-5p, YWHAH, thyroid cancer cell     

Expression and Biologic Significance of Adiponectin Receptors in Papillary Thyroid Carcinoma

Obesity is associated with a higher incidence of thyroid cancer. Adiponectin is one of the most abundant adipokines with a pleiotropic role in metabolism and in the development and progression of cancer. It has been shown that circulating adiponectin level is inversely associated with the risk of thyroid cancer. This study aimed to investigate the possible association between the expression of adiponectin receptors (AdipoR1 and AdipoR2) and clinicopathological variables in papillary thyroid cancer. We found that protein levels of AdipoR1 and AdipoR2 were increased in some thyroid cancer specimens compared with adjacent normal thyroid tissues. Thyroid cancer cells expressed AdipoR1 and AdipoR2, which were attenuated by histone deacetylase inhibitors valproic acid and trichostatin A. Adiponectin stimulated AMP-activated protein kinase phosphorylation in thyroid cancer cells. We further determined the expression of AdipoR1 and AdipoR2 by immunohistochemical staining in primary tumor samples and metastatic lymph nodes. AdipoR1 was expressed in 27 % of primary tumors and AdipoR2 in 47 %. Negative expression of both adiponectin receptors was significantly associated with extrathyroidal invasion, multicentricity, and higher TNM stage. There was a trend toward decreased disease-free survival in patients with negative tumor expression of AdipoR1 and AdipoR2 (log-rank P = 0.051). Collectively, overexpression of adiponectin receptors was observed in some tumor tissues of papillary thyroid cancer and was associated with a better prognosis.     

MiR-20a Is Upregulated in Anaplastic Thyroid Cancer and Targets LIMK1

Background

There have been conflicting reports regarding the function of miR-20a in a variety of cancer types and we previously found it to be dysregulated in sporadic versus familial papillary thyroid cancer. In this study, we studied the expression of miR-20a in normal, benign and malignant thyroid samples, and its effect on thyroid cancer cells in vitro and in vivo.

Methodology/Principal Findings

The expression of miR-20a in normal, benign and malignant thyroid tissue was determined by quantitative RT-PCR. Thyroid cancer cells were transfected with miR-20a and the effect on cellular proliferation, tumor spheroid formation, and invasion was evaluated. Target genes of miR-20 were determined by genome-wide mRNA expression analysis with miR-20a overexpression in thyroid cancer cells and target prediction database. Target genes were validated by quantitative PCR and immunoblotting, and luciferase assays. MiR-20a expression was significantly higher in anaplastic thyroid cancer than in differentiated thyroid cancer, and benign and normal thyroid tissues. MiR-20a significantly inhibited thyroid cancer cell proliferation in vitro (p<0.01) and in vivo (p<0.01), tumor spheroid formation (p<0.05) and invasion (p<0.05) in multiple thyroid cancer cell lines. We found that LIMK1 was a target of miR-20a in thyroid cancer cell lines and direct knockdown of LIMK1 recapitulated the effect of miR-20a in thyroid cancer cells.

Conclusions/Significance

To our knowledge, this is the first study to demonstrate that miR-20a plays a role as a tumor suppressor in thyroid cancer cells and targets LIMK1. Our findings suggest the upregulated expression of miR-20a in anaplastic thyroid cancer counteracts thyroid cancer progression and may have therapeutic potential.     

Loss of BRCA1-A complex function in RAP80 null tumor cells

Receptor Associated Protein 80 (RAP80) is a subunit of the BRCA1-A complex and targets BRCA1 to DNA damage sites in response to DNA double strand breaks. Since mutations of BRCA1 are associated with familial ovarian cancers, we screened 26 ovarian cancer-derived cell lines for RAP80 mutations and found that TOV-21G cells harbor a RAP80 mutation (c.1107G >A). This mutation generates a stop codon at Trp369, which deletes the partial AIR region and the C-terminal zinc fingers of RAP80. Interestingly, both the mutant and wild type alleles of RAP80 lose their expression due to promoter hypermethylation, suggesting that TOV-21G is a RAP80-null cell line. In these cells, not only is the BRCA1-A complex disrupted, but the relocation of the remaining subunits in the BRCA1-A complex including BRCA1, CCDC98, NBA1, BRCC36 and BRE is significantly suppressed. Moreover, TOV-21G cells are hypersensitive to ionizing radiation, which is due to the compromised DNA damage repair capacity in these cells. Reconstitution of TOV-21G cells with wild type RAP80 rescues these cellular defects in response to DNA damage. Thus, our results demonstrate that RAP80 is a scaffold protein in the BRCA1-A complex. Identification of TOV-21G as a RAP80 null tumor cell line will be very useful for the study of the molecular mechanism in DNA damage response.     

Disease-Specific Mortality and Secondary Primary Cancer in Well-Differentiated Thyroid Cancer with Type 2 Diabetes Mellitus

Background

Increased body mass index is related to the incidence of thyroid cancer. However, the presentation and therapeutic outcomes of different thyroid cancers and type 2 diabetes mellitus (DM) have not been studied. This study investigated the effect of type 2 DM on the clinical presentations and therapeutic outcome of well-differentiated thyroid cancer.

Methods and Findings

A retrospective analysis of adult thyroid cancer patients with or without type 2 DM admitted between January 2001 and December 2010 was performed at an institution. A total of 1,687 well-differentiated thyroid cancer patients with different histological patterns were enrolled. Among these subjects, 122 were type 2 DM patients. Patients with thyroid cancer and type 2 DM were significantly older than non-DM patients. After a mean follow-up period of 5.6±0.1 years, patients with thyroid cancer and type 2 DM showed a higher percentage of disease progression than non-DM patients (24.6% vs. 17.4%). In addition, disease-specific mortality was higher in the type 2 DM group (10.7% vs. 3.8%). Thyroid cancer patients with type 2 DM showed a higher percentage of secondary primary cancers than those without DM (10.7% vs. 4.9%). Thyroid cancer-specific survival rates in the type 2 DM and non-DM groups were 82.2% and 94.9% at 5 years, 72.9% and 91.4% at 10 years, and 36.5% and 61.3% at 20 years, respectively. Multivariate analysis showed that type 2 DM was independent of thyroid cancer-specific mortality.

Conclusion

Patients with type 2 DM and well-differentiated thyroid cancer had an advanced tumor-node-metastasis stage at the time of diagnosis and an increased disease-specific mortality. Aggressive surgical procedures and close follow-up for well-differentiated thyroid cancer patients with type 2 DM are therefore necessary.     

Thyrotropin and serum regulate thyroid cell proliferation through differential effects on p27 expression and localization

Thyroid cell proliferation is regulated by the concerted action of TSH/cAMP and serum growth factors. The specific contributions of cAMP-dependent vs. -independent signals to cell cycle progression are not well understood. We examined the molecular basis for the synergistic effects of TSH and serum on G1/S phase cell cycle progression in rat thyroid cells. Although strictly required for thyroid cell proliferation, TSH failed to stimulate G1 phase cell cycle progression. Together with serum, TSH increased the number of cycling cells. TSH enhanced the effects of serum on retinoblastoma protein hyperphosphorylation, cyclin-dependent kinase 2 activity, and cyclin A expression. Most notably, TSH and serum elicited strikingly different effects on p27 localization. TSH stimulated the nuclear accumulation of p27, whereas serum induced its nuclear export. Unexpectedly, TSH enhanced the depletion of nuclear p27 in serum-treated cells. Furthermore, only combined treatment with TSH and serum led to rapamycin-sensitive p27 turnover. Together, TSH and serum stimulated p70S6K activity that remained high through S phase. These data suggest that TSH regulates cell cycle progression, in part, by increasing the number of cycling cells through p70S6K-mediated effects on the localization of p27.     

Activation of the RhoB Signaling Pathway by Thyroid Hormone Receptor β in Thyroid Cancer Cells

Thyroid hormone receptor (TR) mediates the crucial effects of the thyroid hormone (T3) on cellular growth, development, and differentiation. Decreased expression or inactivating somatic mutations of TRs have been found in human cancers of the liver, breast, lung, and thyroid. The mechanisms of TR-associated carcinogenesis are still not clear. To establish the function of TRβ in thyroid cancer cell proliferation, we constructed a recombinant adenovirus vector, AdTRβ, which expresses human TRβ1 cDNA. Thyroid cancer cell lines in which TRβ protein levels were significantly decreased as compared to intact thyroid tissues were infected with AdTRβ and the function of TRβ on cell proliferation and migration was analyzed. Ligand-bound TRβ induced HDAC1 and HDAC3 dissociation from, and histone acetylation associated with the RhoB promoter and enhanced the expression of RhoB mRNA and protein. In AdTRβ-infected cells, T3 and farnesyl transferase inhibitor (FTI)-treatment induced the distribution of RhoB on the cell membrane and enhanced the abundance of active GTP-bound RhoB. This RhoB protein led to p21-associated cell-cycle arrest in the G0/G1 phase, following inhibition of cell proliferation and invasion. Conversely, lowering cellular RhoB by small interfering RNA knockdown in AdTRβ-infected cells led to downregulation of p21 and inhibited cell-cycle arrest. The growth of BHP18-21v tumor xenografts in vivo was significantly inhibited by AdTRβ injection with FTIs-treatment, as compared to control virus-injected tumors. This novel signaling pathway triggered by ligand-bound TRβ provides insight into possible mechanisms of proliferation and invasion of thyroid cancer and may provide new therapeutic targets for thyroid cancers.     

Biological activity of the mammalian RAP genes in yeast.

We have screened expression libraries for mammalian cDNAs capable of suppressing defects in ras1- Schizosaccharomyces pombe. Both the RAP1A and RAP1B genes were identified in this manner. They suppress defects in cell morphology and sporulation, although not conjugation. In contrast, RAP genes do not suppress phenotypes in the yeast Saccharomyces cerevisiae that are deficient in RAS. Indeed, expression of RAP1A appears to antagonize the activated S. cerevisiae RAS2val19 gene. These results indicate that RAP proteins can interact with RAS targets, sometimes productively, sometimes nonproductively.     

Expression and distribution of S-100, CD83 and apoptosis-related proteins (Fas, FasL and Bcl-2) in tissues of thyroid carcinoma

Previous studies have shown that dendritic cells (DCs) and apoptosis play a critical role in the pathogenesis of thyroid carcinoma (TC). This study was designed to investigate the expression and distribution of S-100 protein, CD83 and apoptosis-related proteins (Fas, FasL and Bcl-2) in the thyroid tissues of thyroid papillary carcinoma (TPC) and their role in TPC pathogenesis. Immunohistochemical staining techniques and other methods were used on pathological tissues of 30 patients with Thyroid papillary carcinoma (TPC) and 30 cases of thyroid follicular adenoma (TFA,as control) to detect the expression and distribution of S-100 protein, CD83, Fas, FasL and Bcl-2. A higher expression of S-100 protein in TPC (4.6+/-3.2%) vs.TFA (0.95+/-0.64%) (p<0.001) was observed as well as a higher expression of CD83 in the peri-cancerous tissues (PCT) (32.51+/-22.32) vs. TFA (5.19+/-8.08) (p<0.001), oppositely, CD83 was negative in the cancerous net.TPC showed greater increases in levels of Fas, FasL and Bcl-2 than did the TFA. Our findings suggest that impaired immune function, absence of CD83-positive mature and activated dendritic cells in cancer nodules may have a role in the pathogenesis of thyroid papillary carcinoma.The regulation of Fas, FasL and Bcl-2 in TPC may help them evade the immune system.