HIF-1α Expression in BRAFV600E-Positive Papillary Thyroid Microcarcinoma
1
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Background and Objectives: Recent studies have reported that vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF)-1α are up-regulated in BRAF^(V600E)-positive papillary thyroid carcinoma (PTC). We investigated whether papillary thyroid microcarcinomas (PTMCs) also exhibited increased expression of VEGF and HIF-1α. In addition, we analyzed the relationship between BRAF^(V600E) mutation and clinicopathological parameters, as well as HIF-1α expression in PTMC. Materials and Methods: We retrospectively selected 225patients with PTMC. Immunohistochemical staining for HIF-1α and VEGF was performed using paraffinembedded PTMC tissue microarrays. BRAF^(V600E) mutation status was analyzed by dideoxy sequencing. Results:PTMCs larger than 0.5 cm tend to be related to aggressive clinicopathological features such as thyroid capsular invasion (p=0.023) and bilaterality (p=0.047). Immunoreactivity to HIF-1α (20.7%) and VEGF (30.2%) was more prominent in PTMCs as compared to normal follicular cells. However, HIF-1α and VEGF expression was not correlated with clinicopathological features. BRAF^(V600E) mutation was found in 70.7% (159/225) of the PTMC cases. PTMCs harboring the BRAF^(V600E) mutation exhibited larger tumor sizes as compared to PTMCs without the BRAF^(V600E) mutation (p=0.038). However, BRAF^(V600E) mutation status did not correlate with the expression of HIF-1α(p=0.623) or VEGF (p=0.990). Conclusion: HIF-1α and VEGF were more frequently detected in PTMCs as compared to normal thyroid tissues. However, BRAF^(V600E) mutation status was not correlated with the expression of HIF-1α or VEGF in PTMCs.
Abstract
Background and Objectives: Recent studies have reported that vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF)-1α are up-regulated in BRAF^(V600E)-positive papillary thyroid carcinoma (PTC). We investigated whether papillary thyroid microcarcinomas (PTMCs) also exhibited increased expression of VEGF and HIF-1α. In addition, we analyzed the relationship between BRAF^(V600E) mutation and clinicopathological parameters, as well as HIF-1α expression in PTMC. Materials and Methods: We retrospectively selected 225patients with PTMC. Immunohistochemical staining for HIF-1α and VEGF was performed using paraffinembedded PTMC tissue microarrays. BRAF^(V600E) mutation status was analyzed by dideoxy sequencing. Results:PTMCs larger than 0.5 cm tend to be related to aggressive clinicopathological features such as thyroid capsular invasion (p=0.023) and bilaterality (p=0.047). Immunoreactivity to HIF-1α (20.7%) and VEGF (30.2%) was more prominent in PTMCs as compared to normal follicular cells. However, HIF-1α and VEGF expression was not correlated with clinicopathological features. BRAF^(V600E) mutation was found in 70.7% (159/225) of the PTMC cases. PTMCs harboring the BRAF^(V600E) mutation exhibited larger tumor sizes as compared to PTMCs without the BRAF^(V600E) mutation (p=0.038). However, BRAF^(V600E) mutation status did not correlate with the expression of HIF-1α(p=0.623) or VEGF (p=0.990). Conclusion: HIF-1α and VEGF were more frequently detected in PTMCs as compared to normal thyroid tissues. However, BRAF^(V600E) mutation status was not correlated with the expression of HIF-1α or VEGF in PTMCs.
참고문헌 (28)
- DeLellis RA, "Pathology and genetics of thyroid carcinoma", J Surg Oncol, 94(8), pp.662~669 (2006)
- Cappelli C, "Aggressiveness and outcome of papillary thyroid carcinoma (PTC) versus microcarcinoma (PMC): a mono- institutional experience", J Surg Oncol, 95(7), pp.555~560 (2007)
- Chow SM, "Papillary microcarcinoma of the thyroid-Prognostic significance of lymph node metastasis and multifocality", Cancer, 98(1), pp.31~40 (2003)
- Paes JE, "Dysregulation of the phosphatidylinositol 3-kinase pathway in thyroid neoplasia", Endocrinol Metab Clin North Am, 37(2), pp.375~387 (2008)
- Ross JS, "The HER-2", neu oncogene: prognostic factor, predictive factor and target for therapy, 1999, pp.9(2), 125~138
- Liou MJ, "Renal metastasis from papillary thyroid microcarcinoma", Acta Otolaryngol, 125(4), pp.438~442 (2005)
- Adeniran AJ, "Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas", Am J Surg Pathol, 30(2), pp.216~222 (2006)
- Kumar SM, "Mutant V600E BRAF increases hypoxia inducible factor-1alpha expression in melanoma", Cancer Res, 67(7), pp.3177~3184 (2007)
- Volante M, "Goblet cell carcinoids and other mixed neuroendocrine", nonneuroendocrine neoplasms, 2007, pp.451(1), S61~S69
- Mete O, "Controversies in thyroid pathology: thyroid capsule invasion and extrathyroidal extension", Ann Surg Oncol, 17(2), pp.386~391 (2010)
- Edge SB, "The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM", Ann Surg Oncol, 17(6), pp.1471~1474 (2010)
- Hoshino R, "Constitutive activation of the 41-", 43-kDa mitogenactivated protein kinase signaling pathway in human tumors, 1999, pp.18(3), 813~822
- Pao W, "EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib", Proc Natl Acad Sci U S A, 101(36), pp.13306~13311 (2004)
- Jo YS, "Influence of the BRAF V600E mutation on expression of vascular endothelial growth factor in papillary thyroid cancer", J Clin Endocrinol Metab, 91(9), pp.3667~3670 (2006)
- Namba H, "Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers", J Clin Endocrinol Metab, 88(9), pp.4393~4397 (2003)
- Nikiforova MN, "BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas", J Clin Endocrinol Metab, 88(11), pp.5399~5404 (2003)
- Xing M, "BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer", J Clin Endocrinol Metab, 90(12), pp.6373~6379 (2005)
- Tang KT, "BRAF mutation in papillary thyroid carcinoma: pathogenic role and clinical implications", J Chin Med Assoc, 73(3), pp.113~128 (2010)
- Kim TY, "The BRAF mutation is useful for prediction of clinical recurrence in low-risk patients with conventional papillary thyroid carcinoma", Clin Endocrinol, 65(3), pp.364~368 (2006)
- Park YJ, "Papillary microcarcinoma in comparison with larger papillary thyroid carcinoma in BRAF(V600E) mutation, clinicopathological features, and immunohistochemical findings", Head Neck, 32(1), pp.38~45 (2010)
- Liu LX, "Stabilization of vascular endothelial growth factor mRNA by hypoxia-inducible factor 1", Biochem Biophys Res Commun, 291(4), pp.908~914 (2002)
- Miyazawa M, "Association of hypoxia-inducible factor-1 expression with histology in epithelial ovarian tumors: a quantitative analysis of HIF-1", Arch Gynecol Obstet, 279(6), pp.789~796 (2009)
- Simiantonaki N, "Hypoxia-inducible factor 1 alpha expression increases during colorectal carcinogenesis and tumor progression", BMC Cancer, 8, pp.320~ (2008)
- Yan M, "BRCA1 tumours correlate with a HIF-1alpha phenotype and have a poor prognosis through modulation of hydroxylase enzyme profile expression", Br J Cancer, 101(7), pp.1168~1174 (2009)
- Zerilli M, "BRAF(V600E) mutation influences hypoxiainducible factor-1alpha expression levels in papillary thyroid cancer", Mod Pathol, 23(8), pp.1052~1060 (2010)
- Kunz M, "Molecular responses to hypoxia in tumor cells", Mol Cancer, 2, pp.23~ (2003)
- Lim JH, "Ras-dependent induction of HIF-1alpha785 via the Raf", MEK, Oncogene, pp.2004, 23(58)[DOI]
- Chun YS, "Phorbol ester stimulates the nonhypoxic induction of a novel hypoxia-inducible factor 1alpha isoform: implications for tumor promotion", Cancer Res, 63(24), pp.8700~8707 (2003)