Biomarker Commons

Sphingosine kinase 1 is overexpressed and promotes proliferation in human thyroid cancer.

Mol Endocrinol. 2011 Nov;25(11):1858-66

Authors: Guan H, Liu L, Cai J, Liu J, Ye C, Li M, Li Y

Abstract
Sphingosine kinase 1 (SphK1), an oncogenic kinase, has been previously found to be elevated in various types of human cancer and play a role in tumor development and progression. Nevertheless, the biological and clinical significance of SphK1 in thyroid cancer is largely unknown. Here, we demonstrate that the expression of SphK1 is generally up-regulated in thyroid cancer and that its expression level is correlated with the degree of thyroid malignancy. Silencing SphK1 by specific RNA interference is able to suppress the proliferation of thyroid cancer cells, and SphK1 expression level is strongly associated with the expression of proliferation cell nuclear antigen in thyroid cancer tissues. Of particular note is that depletion of SphK1 results in dephosphorylation of protein kinase B and glycogen synthase kinase-3β and subsequent inactivation of β-catenin-T-cell factor/lymphoid enhancing factor transcriptional activity. Hence, taken together, our study has identified SphK1 as a proproliferative oncogenic kinase, an Akt/glycogen synthase kinase-3β/β-catenin activator, and probably a biomarker for thyroid cancer as well.

PMID: 21940753 [PubMed - indexed for MEDLINE]

Survivin-deltaEx3: a novel biomarker for diagnosis of papillary thyroid carcinoma.

J Cancer Res Ther. 2011 Jul;7(3):325-30

Authors: Vandghanooni S, Eskandani M, Montazeri V, Halimi M, Babaei E, Feizi MA

Abstract
CONTEXT: The most important problem in the case of thyroid nodules is the lack of suitable criteria for detecting malignant thyroid tumors from other nodules in the early stage. Variable expressions level of survivin, an inhibitory protein in apoptotic pathway, and its splice variants in malignant carcinoma versus well-differentiated normal tissues candidate them as reliable biomarkers in cancers.
AIM: To semi-quantitative detection of survivin and its splice variant, survivin-deltaEx3, in thyroid nodules.
SETTING AND DESIGN: We evaluated the expression level of mentioned biomarkers in thyroid nodules including carcinoma.
MATERIALS AND METHODS: Samples were collected from 61 thyroid nodules including malignant, adenoma, non-tumoral (goiter and thyroidities) as well as non-neoplastic normal tissues. Transcriptional levels were measured using semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and the results were normalized to β2microglubin (β2m) gene. Statistical Analysis Used: Independent sample t-test was used to assess the significant variation of expression between different groups.
RESULT: Our data for a first time revealed that survivin-deltaEx3 is significantly up-regulated from normal to malignant thyroid carcinoma tissues (approximately ten fold).
CONCLUSION: High expression level of survivin and survivin-deltaEx3 in malignant papillary thyroid carcinoma suggested survivin gene expression and its splice variant, survivin-deltaEx3, can be potential new markers in diagnosis of human papillary thyroid carcinoma.

PMID: 22044815 [PubMed - indexed for MEDLINE]

Hexokinase III, cyclin A and galectin-3 are overexpressed in malignant follicular thyroid nodules.

Clin Endocrinol (Oxf). 2008 Feb;68(2):252-7

Authors: Hooft L, van der Veldt AA, Hoekstra OS, Boers M, Molthoff CF, van Diest PJ

Abstract
BACKGROUND: Distinguishing malignant thyroid nodules in patients with follicular cytology by fine-needle aspiration (FNA) remains problematic. The large majority of thyroid nodules (> 85%) are overtreated. Therefore, a clear need exists to develop more accurate initial diagnostic tests for follicular thyroid nodules. Galectin-3 is the most recent promising marker to aid discrimination between benign and malignant thyroid lesions; however, this biomarker can be absent in follicular malignancies.
AIMS: This study was undertaken to determine whether additional biomarkers can help to discriminate between benign and malignant thyroid nodules.
METHODS: Surgical specimens of 36 patients with benign (n = 12) and malignant (n = 24) thyroid nodules showing follicular cytology were assessed by immunohistochemistry for the expression of galectin-3 and novel biomarkers.
RESULTS: Expression of hexokinase III (HK III) (P = 0.000) cyclin A (P = 0.002) and galectin-3 (P = 0.003) differed significantly between benign and malignant thyroid nodules. HK III had a sensitivity of 79% [95% confidence interval (CI) 60-91] and a specificity of 100% (95% CI 76-100) in predicting malignancy. Galectin-3 had a sensitivity of 79% (95% CI 56-91) and a specificity of 75% (95% CI 47-91) in predicting malignancy. Combining HK III, cyclin A and galectin-3 in a parallel test increased the sensitivity to 96% (95% CI 80-99) while the specificity remained at a high level of 75% (95% CI 47-91). Leave-one-out cross-validation demonstrated a stable predictive validity of a model based on HK III, cyclin A and galectin-3.
CONCLUSIONS: In this study, we have demonstrated that in addition to galectin-3, HK III and cyclin A profiles could be important biomarkers in predicting malignancy in follicular thyroid nodules. The use of these biomarkers may allow an accurate preoperative diagnosis of thyroid cancer, which can be cost saving and may avoid serious morbidity such as vocal cord paralysis. The value of the suggested biomarkers warrants further evaluation in a large prospective study on cytological samples of follicular thyroid nodules.

PMID: 17868400 [PubMed - indexed for MEDLINE]

Expression of NCAM and OCIAD1 in well-differentiated thyroid carcinoma: correlation with the risk of distant metastasis.

J Clin Pathol. 2012 Mar;65(3):206-12

Authors: Yang AH, Chen JY, Lee CH, Chen JY

Abstract
AIMS: The biomarkers representing the metastatic potential of well-differentiated thyroid carcinoma remain to be established. A study was undertaken to find whether the expression status of neural cell adhesion molecule (NCAM) and/or ovarian cancer immunoreactive antigen domain containing 1 (OCIAD1) is associated with the metastatic potential of differentiated thyroid carcinoma.
METHODS: NCAM and OCIAD1 were analysed by immunohistochemistry on tissue microarrays.
RESULTS: Among 214 well-differentiated thyroid carcinomas, 68 patients had distant metastases. Immunohistochemical analyses showed that the majority of benign thyroid lesions expressed NCAM while a significant proportion of thyroid carcinomas lost or had reduced NCAM expression. Both follicular and papillary carcinomas with distant metastasis had a significantly higher frequency of preserving NCAM expression. Hierarchical clustering analysis showed that OCIAD1 had significant differential expression between benign and malignant thyroid lesions. The overall metastatic-to-localised tumour ratio was higher in NCAM-expressing clusters, but the difference between ratios of OCIAD1-positive and OCIAD1-negative subclusters was not significant.
CONCLUSIONS: These analyses suggest that the preservation of NCAM expression in well-differentiated thyroid carcinoma is an indicator for a higher risk of distant metastasis. OCIAD1 is a potential biomarker of thyroid carcinoma but had no significant additive effect on the risk of distant metastasis. Further elucidation of the molecular mechanisms underlying the NCAM-mediated cellular processes will be beneficial for the development of effective treatments against the metastasis of thyroid carcinoma.

PMID: 22081784 [PubMed - indexed for MEDLINE]

Total oxidant/antioxidant status in sera of patients with thyroid cancers.

Endocr Relat Cancer. 2011 Dec;18(6):773-82

Authors: Wang D, Feng JF, Zeng P, Yang YH, Luo J, Yang YW

Abstract
Oxidative stress is considered to be involved in the pathophysiology of all cancers. In order to evaluate the total oxidant/antioxidant status in patients with thyroid cancer and to investigate the relationship between oxidative stress parameters and serum thyroid profiles among thyroid cancer patients and various controls, we determined oxidative status including total antioxidant status (TAS) and total oxidant status (TOS) and calculation of oxidative stress index (OSI) in sera in 82 thyroid cancer patients, 56 benign thyroid disease patients, and 50 healthy controls. It was found that serum TAS levels were significantly lower in patients with thyroid cancer than in controls (P<0.001), while serum TOS levels and OSI values were significantly higher (both P<0.001) in the cancer patients. No significant correlations were observed between various oxidative stress markers and thyroid profiles in either the thyroid cancer patients or the controls. Receiver operating characteristic curve analysis demonstrated that OSI was the best indicator for distinguishing cancer patients from benign thyroid diseased or healthy controls, followed by TOS and TAS. Risk estimate statistics also indicated that TOS and/or OSI were good risk factors to discriminate patients with thyroid cancer from two controls. These findings suggested that oxidants are increased and antioxidants are decreased in patients with thyroid cancer. OSI may be a more useful oxidative stress biomarker than TAS and TOS for monitoring the clinical status of thyroid cancer patients.

PMID: 22002574 [PubMed - indexed for MEDLINE]

Qualitative and quantitative promoter hypermethylation patterns of the P16, TSHR, RASSF1A and RARβ2 genes in papillary thyroid carcinoma.

Med Oncol. 2011 Dec;28(4):1123-8

Authors: Mohammadi-asl J, Larijani B, Khorgami Z, Tavangar SM, Haghpanah V, Kheirollahi M, Mehdipour P

Abstract
The aim of this study was to evaluate the frequency (as qualitative analysis) and level (as quantitative analysis) of promoter hypermethylation of four genes, P16, TSHR, RASSF1A and RARβ2, and to assess their diagnostic or prognostic values in papillary thyroid tumors. Fifty formalin-fixed paraffin-embedded (FFPE) samples consisting of 25 malignant tumors and 25 non-malignant thyroid tumors were analyzed using COBRA method. Promoter hypermethylation of P16, TESH, RASSF1A and RARB2 genes was noted not only in 10, 7, 19 and 13 cases of malignant tumors, but also it was detected in 7, 11, 23 and 8 cases of benign tumors, respectively, limiting its diagnostic usefulness. The quantitative hypermethylation level was significantly higher in malignant tumors compared to benign tumors for P16 (P<0.004), TSHR (P<0.006) and RASSF1A (P<0.001), but the methylation level of RARβ2 (P<0.31) showed considerable overlap between the two groups. The mean levels of hypermethylation of P16, TSHR and RASSF1A genes were significantly higher in malignant papillary thyroid tumors compared to benign tumors and by choosing the appropriate cutoff for each gene, we could distinguish 9, 9 and 8 PTCs from 25 cases by P16, RASSF1A and TSHR methylation analysis, respectively. According to our results, these three genes, in combination, may be useful as molecular markers. The findings of present study imply that the P16, TSHR and RASSF1A gene promoter hypermethylation may play important roles in the pathogenesis of PTC and can be a potential biomarker for selecting patients with PTC.

PMID: 20535589 [PubMed - indexed for MEDLINE]

Thyroid-specific knockout of the tumor suppressor mitogen-inducible gene 6 activates epidermal growth factor receptor signaling pathways and suppresses nuclear factor-κB activity.

Surgery. 2011 Dec;150(6):1295-302

Authors: Lin CI, Barletta JA, Nehs MA, Morris ZS, Donner DB, Whang EE, Jeong JW, Kimura S, Moore FD, Ruan DT

Abstract
BACKGROUND: Mitogen-inducible gene 6 (Mig-6) is a putative tumor suppressor gene and prognostic biomarker in papillary thyroid cancer. We hypothesized that Mig-6 knockout would activate pro-oncogenic signaling in mouse thyrocytes.
METHODS: We performed a thyroid-specific knockout using the Cre/loxP recombinase system.
RESULTS: Four knockout and 4 control mouse thyroids were harvested at 2 months of age. Immunoblotting confirmed Mig-6 ablation in knockout mice thyrocytes. Epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK) phosphorylation levels were increased in Mig-6 knockout compared to wild-type mice. Total EGFR levels were similar in knockout and wild-type mice. However, EGFR was absent in the caveolae-containing membrane fraction of knockout mice, indicating that Mig-6 depletion is associated with a change in the membrane distribution of EGFR. Although p65 localized to the nucleus in wild-type mice, it was distributed in both cytoplasm and nucleus in knockouts, suggesting that Mig-6 loss decreases p65 activity.
CONCLUSION: Our results confirm the feasibility of targeted, thyroid-specific gene knockout as a strategy for studying the relevance of specific genes in thyroid oncogenesis. We suggest that the loss of Mig-6 alters the membrane distribution of EGFR, which may limit receptor degradation and activate this oncogenic signaling pathway.

PMID: 22136853 [PubMed - indexed for MEDLINE]

XRCC1 polymorphisms and risk of papillary thyroid carcinoma in a Korean sample.

J Korean Med Sci. 2011 Aug;26(8):991-5

Authors: Ryu RA, Tae K, Min HJ, Jeong JH, Cho SH, Lee SH, Ahn YH

Abstract
Polymorphisms of DNA repair genes, X-ray repair cross-complementing group 1 (XRCC1) might contribute to individual susceptibility to different types of cancers. We analyzed the relationship between XRCC1 polymorphisms and the risk of papillary thyroid carcinoma in a Korean sample. A hospital-based case-control study was performed in 111 papillary thyroid carcinoma patients and 100 normal control subjects. XRCC1 Arg194Trp and Arg399Gln single nucleotide polymorphisms (SNPs) were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The XRCC1 Arg194Trp Arg/Trp genotype was significantly associated with a decreased risk of papillary thyroid carcinoma compared to that of Arg/Arg genotype (odds ratio [95% confidence intervals]; 0.550 [0.308-0.983]). There was no significant association between XRCC1 Arg399Gln genotypes and risk of papillary thyroid carcinoma. Based on these results, the XRCC1 Arg194Trp Arg/Trp genotype could be used as a useful molecular biomarker to predict genetic susceptibility for papillary thyroid carcinoma in Koreans.

PMID: 21860547 [PubMed - indexed for MEDLINE]