PubMed Health⌕ Search

Biomedical subjects

Massimo Santoro

Publications and source records attributed to Massimo Santoro.

At least 19 recordsLinked to original sources
PubMed2007

Prevalence of spinocerebellar ataxia type 2 mutation among Italian Parkinsonian patients.

We evaluated the prevalence of the SCA2 mutation among 224 Italian patients affected by typical Parkinsonism, including 145 sporadic and 79 familial forms. Pink1, Parkin, and LRRK2 gene mutations had been excluded previously. Molecular testing for the CAG expansion at the SCA 2 locus was performed on leukocyte DNA. Cloning and sequencing of the expanded allele was performed in patients positive for the SCA2 expansion. A 38 CAG expansion was detected in 1 of 79 families studied. The proband, a male age 67, and his sister, age 69, were both affected by a benign form of L-dopa-responsive Parkinsonism not associated with cerebellar signs. The inheritance was autosomal dominant. The CAG expansion was stable through meiotic transmission: sequence analysis showed that the CAG stretch was interrupted by 3 CAA. Our study shows that CAG expansion at the SCA 2 locus may represent a genetic cause of familial L-dopa-responsive Parkinsonism among Italian patients. The stability of the pathological CAG expansion detected in this family was related to the presence of CAA interruptions. These findings, together with literature data, suggest that the molecular intrinsic structure of the expanded allele may modulate the phenotypic expression of the SCA2 mutation.

Ataxins↗
PubMed2007

RET/papillary thyroid carcinoma oncogenic signaling through the Rap1 small GTPase.

RET/papillary thyroid carcinoma (PTC) oncoproteins result from the in-frame fusion of the RET receptor tyrosine kinase with protein dimerization motifs encoded by heterologous genes. Here, we show that RET/PTC1 activates the Rap1 small GTPase. The activation of Rap1 was dependent on the phosphorylation of RET Tyr(1062). RET/PTC1 recruited a complex containing growth factor receptor binding protein 2-associated binding protein 1 (Gab1), CrkII (v-crk sarcoma virus CT10 oncogene homologue II), and C3G (Rap guanine nucleotide exchange factor 1). By using dominant-negative and small interfering duplex (small interfering RNA) oligonucleotides, we show that RET/PTC1-mediated Rap1 activation was dependent on CrkII, C3G, and Gab1. Activation of Rap1 was involved in the RET/PTC1-mediated stimulation of the BRAF kinase and the p42/p44 mitogen-activated protein kinases. Proliferation and stress fiber formation of RET/PTC1-expressing PC Cl 3 thyroid follicular cells were inhibited by the dominant-negative Rap1(N17) and by Rap1-specific GTPase-activating protein. Thus, Rap1 is a downstream effector of RET/PTC and may contribute to the transformed phenotype of RET/PTC-expressing thyrocytes.

Actins↗
PubMed2006

A novel pathway of cell growth regulation mediated by a PLA2alpha-derived phosphoinositide metabolite.

The phosphoinositides have well-defined roles in the control of cellular functions, including cytoskeleton dynamics, membrane trafficking, and cell signaling. However, the interplay among the phosphoinositides and their diffusible derivatives that originate through phospholipase A2 action (the lysophosphoinositides and glycerophosphoinositols) remains to be fully elucidated. Here we demonstrate that in PCCl3 rat thyroid cells, the intracellular levels of glycerophosphoinositol are finely modulated by ATP and norepinephrine through the P2Y metabotropic and alpha-adrenergic receptors, respectively. The enzyme involved here is phospholipase A2 IValpha (PLA2 IValpha), which in these cells specifically hydrolyzes phosphatidylinositol, forming lysophosphatidylinositol, glycerophosphoinositol, and arachidonic acid. This receptor-mediated activation of PLA2 IValpha leads to stimulation of PCCl3 cell growth. The involvement of a PLA2 IValpha-mediated pathway is demonstrated by inhibition of the increase in intracellular glycerophosphoinositol levels and cell proliferation by specific inhibitors, RNA interference, and overexpression of the dominant-negative PLA2 IValpha(1-522). Modulation of PCCl3 cell growth is not seen with inhibitors of arachidonic acid metabolism. In conclusion, these data characterize glycerophosphoinositol as a mediator of the purinergic and adrenergic regulation of PCCl3 cell proliferation, defining a novel regulatory cascade specifically involving this soluble phosphoinositide derivative and widening the involvement of the phosphoinositides in the regulation of cell function.

Animals↗
PubMed2006

Structure and chemical inhibition of the RET tyrosine kinase domain.

The RET proto-oncogene encodes a receptor tyrosine kinase for the glial cell line-derived neurotrophic factor family of ligands. Loss-of-function mutations in RET are implicated in Hirschsprung disease, whereas activating mutations in RET are found in human cancers, including familial medullar thyroid carcinoma and multiple endocrine neoplasias 2A and 2B. We report here the biochemical characterization of the human RET tyrosine kinase domain and the structure determination of the non-phosphorylated and phosphorylated forms. Both structures adopt the same active kinase conformation competent to bind ATP and substrate and have a pre-organized activation loop conformation that is independent of phosphorylation status. In agreement with the structural data, enzyme kinetic data show that autophosphorylation produces only a modest increase in activity. Longer forms of RET containing the juxtamembrane domain and C-terminal tail exhibited similar kinetic behavior, implying that there is no cis-inhibitory mechanism within the RET intracellular domain. Our results suggest the existence of alternative inhibitory mechanisms, possibly in trans, for the autoregulation of RET kinase activity. We also present the structures of the RET tyrosine kinase domain bound to two inhibitors, the pyrazolopyrimidine PP1 and the clinically relevant 4-anilinoquinazoline ZD6474. These structures explain why certain multiple endocrine neoplasia 2-associated RET mutants found in patients are resistant to inhibition and form the basis for design of more effective inhibitors.

Animals↗
PubMed2006

The receptor-type protein tyrosine phosphatase J antagonizes the biochemical and biological effects of RET-derived oncoproteins.

Thyroid cancer is frequently associated with the oncogenic conversion of the RET receptor tyrosine kinase. RET gene rearrangements, which lead to the generation of chimeric RET/papillary thyroid carcinoma (PTC) oncogenes, occur in PTC, whereas RET point mutations occur in familial multiple endocrine neoplasia type 2 (MEN2) and sporadic medullary thyroid carcinomas (MTC). We showed previously that the expression of the receptor-type protein tyrosine phosphatase J (PTPRJ) is suppressed in neoplastically transformed follicular thyroid cells. We now report that PTPRJ coimmunoprecipitates with wild-type RET and with the MEN2A-associated RET(C634R) oncoprotein but not with the RET/PTC1 and RET-MEN2B isoforms. Using mutated forms of PTPRJ and RET-MEN2A, we show that the integrity of the respective catalytic domains is required for the PTPRJ/RET-MEN2A interaction. PTPRJ expression induces dephosphorylation of the RET(C634R) and, probably via an indirect mechanism, RET/PTC1 oncoproteins on two key RET autophosphorylation sites (Tyr1062 and Tyr905). This results in a significant decrease of RET-induced Shc and extracellular signal-regulated kinase 1/2 phosphorylation levels. In line with this finding, adoptive PTPRJ expression reduced the oncogenic activity of RET(C634R) in an in vitro focus formation assay of NIH3T3 cells. As expected from the coimmunoprecipitation results, the RET(M918T) oncoprotein, which is associated to MEN2B and sporadic MTC, was resistant to the dephosphorylating activity of PTPRJ. Taken together, these findings identify RET as a novel substrate of PTPRJ and suggest that PTPRJ expression levels may affect tumor phenotype associated with RET/PTC1 and RET(C634R) mutants. On the other hand, resistance to PTPRJ may be part of the mechanism of RET oncogenic conversion secondary to the M918T mutation.

Cell Line, Tumor↗
PubMed2006

Abnormal interactions of calsequestrin with the ryanodine receptor calcium release channel complex linked to exercise-induced sudden cardiac death.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmogenic disorder associated with mutations in the cardiac ryanodine receptor (RyR2) and cardiac calsequestrin (CASQ2) genes. Previous in vitro studies suggested that RyR2 and CASQ2 interact as parts of a multimolecular Ca(2+)-signaling complex; however, direct evidence for such interactions and their potential significance to myocardial function remain to be determined. We identified a novel CASQ2 mutation in a young female with a structurally normal heart and unexplained syncopal episodes. This mutation results in the nonconservative substitution of glutamine for arginine at amino acid 33 of CASQ2 (R33Q). Adenoviral-mediated expression of CASQ2(R33Q) in adult rat myocytes led to an increase in excitation-contraction coupling gain and to more frequent occurrences of spontaneous propagating (Ca2+ waves) and local Ca2+ signals (sparks) with respect to control cells expressing wild-type CASQ2 (CASQ2WT). As revealed by a Ca2+ indicator entrapped inside the sarcoplasmic reticulum (SR) of permeabilized myocytes, the increased occurrence of spontaneous Ca2+ sparks and waves was associated with a dramatic decrease in intra-SR [Ca2+]. Recombinant CASQ2WT and CASQ2R33Q exhibited similar Ca(2+)-binding capacities in vitro; however, the mutant protein lacked the ability of its WT counterpart to inhibit RyR2 activity at low luminal [Ca2+] in planar lipid bilayers. We conclude that the R33Q mutation disrupts interactions of CASQ2 with the RyR2 channel complex and impairs regulation of RyR2 by luminal Ca2+. These results show that intracellular Ca2+ cycling in normal heart relies on an intricate interplay of CASQ2 with the proteins of the RyR2 channel complex and that disruption of these interactions can lead to cardiac arrhythmia.

Amino Acid Substitution↗
PubMed2006

RET/papillary thyroid cancer rearrangement in nonneoplastic thyrocytes: follicular cells of Hashimoto's thyroiditis share low-level recombination events with a subset of papillary carcinoma.

CONTEXT: RET/papillary thyroid cancer (PTC) is a marker for papillary thyroid carcinoma, but its specificity has been questioned because of the disputed identification of RET/PTC in Hashimoto's thyroiditis (HT), oncocytic tumors, and other thyroid lesions. OBJECTIVE: The objective of this study was to determine 1) whether RET/PTC occurs in nonneoplastic follicular cells of HT, and 2) its recombination rate in thyroid tumors. DESIGN/PATIENTS: Forty-three samples from 31 cases of HT were examined using interphase fluorescence in situ hybridization (FISH) with RET probes spanning the breakpoint region; real-time RT-PCR to quantify RET/PTC1, RET/PTC3, and c-RET transcripts; and RT-PCR after laser capture microdissection to enrich samples for follicular cells. The results were compared with those similarly obtained in 34 papillary carcinomas, eight thyroid oncocytic tumors, and 21 normal thyroids. RESULTS: Normal samples showed no RET rearrangement. Sixty-eight percent (15 of 22) of HT were positive by FISH; in all thyroiditis, signals were localized to rare nonneoplastic follicular cells; low-level RET/PTC was identified in 17% (five of 29) of thyroiditis cases by real-time RT-PCR and in an additional six of 11 real-time negative cases after increasing sensitivity with laser capture microdissection. Low RET/PTC1 levels were detected in 26% (nine of 34) of papillary carcinomas with an expression pattern and proportion of FISH-positive cells similar to those of the thyroiditis. Forty-seven percent (16 of 34) of papillary carcinomas and one oncocytic carcinoma expressed high RET/PTC1 mRNA levels. CONCLUSIONS: Low-level RET/PTC recombination occurs in nonneoplastic follicular cells in HT and in a subset of papillary thyroid carcinomas. RET/PTC expression variability should be taken into account for the molecular diagnosis of thyroid lesions. Overlapping molecular mechanisms may govern early stages of tumor development and inflammation in the thyroid.

Carcinoma, Papillary↗
PubMed2006

BAY 43-9006 inhibition of oncogenic RET mutants.

BACKGROUND: Medullary and papillary thyroid carcinomas are often associated with oncogenic activation of the RET tyrosine kinase. We evaluated whether the biaryl urea BAY 43-9006, which is known to inhibit several other tyrosine kinases, blocks RET kinase function and oncogenic activity. METHODS: We examined BAY 43-9006 activity against oncogenic RET in vitro and in cellular RET signaling in oncogenic RET-transfected NIH3T3 fibroblasts by using immunocomplex kinase assays and immunoblotting with phospho-specific antibodies. The effects of BAY 43-9006 on proliferation of human TPC1 and TT thyroid carcinoma cells, which harbor spontaneous oncogenic RET alleles, and on RAT1 fibroblasts transformed with oncogenic RET mutants, including mutants that are resistant to other chemotherapeutic agents, were determined using growth curves and flow cytometry. Growth of TT cell-derived xenograft tumors in athymic mice treated orally with BAY 43-9006 or with vehicle was measured. All statistical tests were two-sided. RESULTS: BAY 43-9006 inhibited oncogenic RET kinase activity at half-maximal inhibitory concentrations (IC50s) of 50 nM or less in NIH3T3 cells. It also arrested the growth of NIH3T3 and RAT1 fibroblasts transformed by oncogenic RET and of thyroid carcinoma cells that harbor spontaneous oncogenic RET alleles. Moreover, BAY 43-9006 inhibited the growth of cells carrying RET V804L (IC50 = 110 nM, 95% confidence interval [CI] = 88 to 133 nM) or RET V804M (IC50 = 147 nM, 95% CI = 123 nM to 170 nM), both mutants that are resistant to anilinoquinazolines and pyrazolopyrimidines. After 3 weeks of oral treatment with BAY 43-9006 (60 mg/kg/day), the volume of TT cell xenografts (n = 7) was reduced from 72.5 to 44 mm3 (difference = 28.5 mm3, 95% CI = 7 mm3 to 50 mm3), whereas in vehicle-treated mice (n = 7), mean tumor volume increased to 408 mm3 (difference = 320 mm3, 95% CI = 180 mm3 to 460 mm3; untreated versus treated, P =.02). This inhibition paralleled a decrease in RET phosphorylation. CONCLUSIONS: BAY 43-9006 is a powerful inhibitor of the RET kinase. Its potential as a therapeutic tool for RET-positive thyroid tumors, including those expressing V804 mutations merits study.

Administration, Oral↗
PubMed2006

BRAF is a therapeutic target in aggressive thyroid carcinoma.

PURPOSE: Oncogenic conversion of BRAF occurs in approximately 44% of papillary thyroid carcinomas and 24% of anaplastic thyroid carcinomas. In papillary thyroid carcinomas, this mutation is associated with an unfavorable clinicopathologic outcome. Our aim was to exploit BRAF as a potential therapeutic target for thyroid carcinoma. EXPERIMENTAL DESIGN: We used RNA interference to evaluate the effect of BRAF knockdown in the human anaplastic thyroid carcinoma cell lines FRO and ARO carrying the BRAF V600E (V600EBRAF) mutation. We also exploited the effect of BAY 43-9006 [N-(3-trifluoromethyl-4-chlorophenyl)-N'-(4-(2-methylcarbamoyl pyridin-4-yl)oxyphenyl)urea], a multikinase inhibitor able to inhibit RAF family kinases in a panel of six (V600E)BRAF-positive thyroid carcinoma cell lines and in nude mice bearing ARO cell xenografts. Statistical tests were two sided. RESULTS: Knockdown of BRAF by small inhibitory duplex RNA, but not control small inhibitory duplex RNA, inhibited the mitogen-activated protein kinase signaling cascade and the growth of ARO and FRO cells (P < 0.0001). These effects were mimicked by thyroid carcinoma cell treatment with BAY 43-9006 (IC50 = 0.5-1 micromol/L; P < 0.0001), whereas the compound had negligible effects in normal thyrocytes. ARO cell tumor xenografts were significantly (P < 0.0001) smaller in nude mice treated with BAY 43-9006 than in control mice. This inhibition was associated with suppression of phospho-mitogen-activated protein kinase levels. CONCLUSIONS: BRAF provides signals crucial for proliferation of thyroid carcinoma cells spontaneously harboring the (V600E)BRAF mutation and, therefore, BRAF suppression might have therapeutic potential in (V600E)BRAF-positive thyroid cancer.

Animals↗
PubMed2006

Activation of the Erk8 mitogen-activated protein (MAP) kinase by RET/PTC3, a constitutively active form of the RET proto-oncogene.

Mitogen-activated protein (MAP) kinases have a central role in several biological functions, including cell adhesion and spreading, chemotaxis, cell cycle progression, differentiation, and apoptosis. Extracellular signal-regulated kinase 8 (Erk8) is a large MAP kinase whose activity is controlled by serum and the c-Src non-receptor tyrosine kinase. Here, we show that RET/PTC3, an activated form of the RET proto-oncogene, was able to activate Erk8, and we demonstrate that such MAP kinase participated in RET/PTC3-dependent stimulation of the c-jun promoter. By using RET/PTC3 molecules mutated in specific tyrosine autophosphorylation sites, we characterized Tyr(981), a known binding site for c-Src, as a major determinant of RET/PTC3-induced Erk8 activation, although, surprisingly, the underlying mechanism did not strictly depend on the activity of Src. In contrast, we present evidence that RET/PTC3 acts on Erk8 through Tyr(981)-mediated activation of c-Abl. Furthermore, we localized the region responsible for the modulation of Erk8 activity by the RET/PTC3 and Abl oncogenes in the Erk8 C-terminal domain. Altogether, these results support a role for Erk8 as a novel effector of RET/PTC3 and, therefore, RET biological functions.

Amino Acid Sequence↗
PubMed2006

Drug insight: Small-molecule inhibitors of protein kinases in the treatment of thyroid cancer.

Molecular targeting of protein kinases is a new paradigm in the treatment of cancer. The clinical efficacy of low-molecular weight inhibitors of ABL, stem-cell growth-factor receptor, and the epidermal growth factor receptor in different tumor types is witness to the power of this approach. The presence of activating mutations of a kinase, or an increased gene copy number, might anticipate tumor responsiveness to its targeting. Thyroid cancer is the most prevalent endocrine malignancy and is frequently associated with the oncogenic conversion of two specific protein kinases, RET and BRAF. Small-molecule inhibitors of both kinases have already reached the clinical testing stage. Protein kinases other than RET and BRAF are also being evaluated for their potential in thyroid-cancer treatment.

Adenocarcinoma, Follicular↗
PubMed2006

RET/PTC activation in papillary thyroid carcinoma: European Journal of Endocrinology Prize Lecture.

Papillary thyroid carcinoma (PTC) is frequently associated with RET gene rearrangements that generate the so-called RET/PTC oncogenes. In this review, we examine the data about the mechanisms of thyroid cell transformation, activation of downstream signal transduction pathways and modulation of gene expression induced by RET/PTC. These findings have advanced our understanding of the processes underlying PTC formation and provide the basis for novel therapeutic approaches to this disease.

Animals↗
PubMed2005

Clinical case seminar: in vivo and in vitro characterization of a novel germline RET mutation associated with low-penetrant nonaggressive familial medullary thyroid carcinoma.

CONTEXT: RET mutation analysis provides useful information on the clinical outcome of medullary thyroid carcinomas (MTCs) and the risk of disease in the family members. OBJECTIVE: The objective of this study was to document genotype-phenotype relationships in an Italian family with a novel RET mutation. DESIGN/SETTING: RET gene alterations were investigated in a patient with unifocal MTC and her relatives. The identified mutation was subjected to in vitro functional testing. PATIENTS: Patients included a female proband who developed MTC at age 60, her five children, and three grandchildren. MAIN OUTCOME MEASURES: DNA extracted from the blood and the proband's tumor were analyzed for RET alterations. The transforming potential and mitogenic properties of the identified mutation were investigated. RESULTS: A novel heterozygous germline RET mutation at codon 777 (AAC-->AGC, N-->S) (RET/N777S) was identified in the proband and three of her relatives. Two of the latter presented thyroid nodules, but none had MTC or C cell hyperplasia. The proband's MTC was characterized by late onset and limited aggressiveness, with no evidence of regional lymph node or distant metastases 10 yr after total thyroidectomy. This phenotype is consistent with the RET/N777S mutant's low-grade transforming potential and limited activation of RET tyrosine kinase. CONCLUSION: Our findings indicate that the newly identified RET/N777S mutation is a low-penetrant cause of MTC disease. This phenotype might be less aggressive than that associated with MEN2A of familial MTC, although close clinical follow-up of carriers is essential.

Carcinoma, Medullary↗
PubMed2005

Mutation of the PIK3CA gene in anaplastic thyroid cancer.

The phosphatidylinositol 3'-kinase (PI3K) pathway is frequently activated in thyroid carcinomas through the constitutive activation of stimulatory molecules (e.g., Ras) and/or the loss of expression and/or function of the inhibitory PTEN protein that results in Akt activation. Recently, it has been reported that somatic mutations within the PI3K catalytic subunit, PIK3CA, are common (25-40%) among colorectal, gastric, breast, ovarian cancers, and high-grade brain tumors. Moreover, PIK3CA mutations have a tendency to cluster within the helical (exon 9) and the kinase (exon 20) domains. In this study, 13 thyroid cancer cell lines, 80 well-differentiated thyroid carcinomas of follicular (WDFC) and papillary (WDPC) type, and 70 anaplastic thyroid carcinomas (ATC) were investigated, by PCR-direct sequencing, for activating PIK3CA mutations at exons 9 and 20. Nonsynonymous somatic mutations were found in 16 ATC (23%), two WDFC (8%), and one WDPC (2%). In 18 of the 20 ATC cases showing coexisting differentiated carcinoma, mutations, when present, were restricted to the ATC component and located primarily within the kinase domain. Three cell lines of papillary and follicular lineage (K1, K2, and K5) were also found mutated. In addition, activation of Akt was observed in most of the ATC harboring PIK3CA mutations. These findings indicate that mutant PIK3CA is likely to function as an oncogene among ATC and less frequently well-differentiated thyroid carcinomas. The data also argue for a role of PIK3CA targeting in the treatment of ATC patients.

Adenocarcinoma, Follicular↗
PubMed2005

Overexpression of the cytokine osteopontin identifies aggressive laryngeal squamous cell carcinomas and enhances carcinoma cell proliferation and invasiveness.

PURPOSE: Osteopontin is a secreted cytokine that binds to the cell surface CD44v6 receptor. We studied osteopontin and CD44v6 expression in laryngeal squamous cell carcinomas and correlated osteopontin expression levels with clinicopathologic tumor features. EXPERIMENTAL DESIGN: We used immunohistochemistry, immunoblotting, and reverse transcription-PCR to study osteopontin expression in 58 laryngeal squamous cell carcinomas. Cultured squamous carcinoma cells were treated with exogenous osteopontin or with RNA interference to knockdown osteopontin expression. RESULTS: Osteopontin expression was higher in all the invasive carcinomas than in patient-matched normal mucosa. Its expression levels were significantly correlated with tumor stage and grade and with the presence of lymph node and distant metastases. Osteopontin positivity was negatively correlated with overall survival (P = 0.03). Osteopontin expression was paralleled by intense cell surface reactivity for CD44v6. Treatment of squamous carcinoma cells with recombinant osteopontin sharply increased proliferation and Matrigel invasion in comparison with the untreated cells parallel to activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/mitogen-activated protein kinase signaling cascade. Osteopontin knockdown by RNA interference, anti-CD44 antibodies, and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibition prevented these effects. CONCLUSIONS: These results identify osteopontin as a marker and a potential therapeutic target in cases of aggressive laryngeal squamous cell carcinomas.

Adult↗
PubMed2005

RAI(ShcC/N-Shc)-dependent recruitment of GAB 1 to RET oncoproteins potentiates PI 3-K signalling in thyroid tumors.

RAI, also named ShcC/N-Shc, one of the members of the Shc proteins family, is a substrate of the RET receptor tyrosine kinase. Here, we show that RAI forms a protein complex with both RET/MEN 2 A and RET/PTC oncoproteins. By co-immunoprecipitation, we found that RAI associates with the Grb 2-associated binder 1 (GAB 1) adapter. This association is constitutive, but, in the presence of RET oncoproteins, both RAI and GAB 1 are tyrosine-phosphorylated, and the stoichiometry of this interaction remarkably increases. Consequently, the p 85 regulatory subunit of phosphatidylinositol-3 kinase (PI-3 K) is recruited to the complex, and its downstream effector Akt is activated. We show that human thyroid cancer cell lines derived from papillary or medullary thyroid carcinoma (PTC or MTC) carrying, respectively, RET/PTC and RET/MEN 2 A oncoproteins express RAI proteins. We also show that human PTC samples express higher levels of RAI, when compared to normal thyroid tissue. In thyroid cells expressing RET/PTC 1, ectopic expression of RAI protects cells from apoptosis; on the other hand, the silencing of endogenous RAI by small inhibitory duplex RNAs in a PTC cell line that expresses endogenous RET/PTC 1, increases the rate of spontaneous apoptosis. These data suggest that RAI is a critical substrate for RET oncoproteins in thyroid carcinomas.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Osteopontin expression and prognostic significance in non-small cell lung cancer.

PURPOSE: The survival rate of non-small cell lung cancer patients is very low, and knowledge of predictors of outcome is inadequate. To improve the curability of lung cancer, we need to identify new specific molecules involved in tumorigenesis and progression. The purpose of this study was to better define the role of osteopontin in non-small cell lung cancer biology by determining its prognostic significance. EXPERIMENTAL DESIGN: Osteopontin expression was evaluated by immunohistochemistry, as percentage of neoplastic cells with cytoplasmic immunoreactivity, in a wide series of patients with stage I-IIIA non-small cell lung cancer (207 cases). The median value of this series (20% of positive cells) was used as the cutoff value to distinguish tumors with low (<20%) from tumors with high (> or =20%) osteopontin expression. RESULTS: Taking the series of patients as a whole (207 cases), osteopontin expression was associated with neither overall survival (P = 0.14) nor disease-free survival (P = 0.074). However, among patients with at least 6 years of follow-up (163 cases), 6-year overall survival and disease-free survival were significantly reduced if osteopontin expression was high (P = 0.0085 for overall survival, P = 0.0023 for disease-free survival). Moreover, a statistically significant correlation between high levels of osteopontin and shorter overall survival (P = 0.034) and disease-free survival (P = 0.011) in patients with stage I tumors (136 cases) was shown. CONCLUSIONS: Our results support the hypothesis of an association between high osteopontin expression and poor survival of patients with stage I non-small cell lung cancer, suggesting that osteopontin could be a candidate target for cancer therapy.

Adult↗