目的 探讨抑癌基因肿瘤高甲基化基因1(hypermethylated in cancer 1, HIC-1)和致癌基因透明质酸介导的细胞游走受体(hyaluronan-mediated motility receptor, HMMR)在乳腺小叶增生、乳腺纤维腺瘤和乳腺癌组织中的表达情况,及其与乳腺癌临床病理参数间的关系。方法 应用免疫组织化学方法检测57例患者的乳腺手术切除标本(其中乳腺小叶增生17例,乳腺纤维腺瘤及乳腺癌各20例)中HIC-1与HMMR蛋白的表达情况,观察其染色结果以半定量分析,并结合临床病理学指标进行相关分析。结果 ①乳腺小叶增生和乳腺纤维腺瘤组织中HIC-1蛋白表达呈中度阳性(平均计分均为5.65分);而乳腺癌组织中HIC-1表达减弱,呈弱阳性(平均计分为2.15分),二者间差异有统计学意义(P<0.001)。②乳腺小叶增生和纤维腺瘤组织中的HMMR均呈低表达(其中纤维腺瘤平均计分为0.3分,小叶增生平均积分为0),而乳腺癌组织中HMMR表达呈弱阳性(平均计分为2.3分),二者间差异有统计学意义(P<0.001)。③ HIC-1 及HMMR蛋白的表达与乳腺癌相关临床病理特征之间未见明显关联。结论 抑癌基因HIC-1蛋白在乳腺癌组织中呈明显低表达,而致癌基因HMMR在乳腺癌组织中呈较高表达,HIC-1及受HIC-1调控的下游基因HMMR可能与乳腺恶性肿瘤的发生、发展有关。
Objective: To study the expression of tumor suppressor gene hypermethylated in cancer 1(HIC-1)and oncogene hyaluronan-mediated motility receptor (HMMR) in lobular hyperplasia of mammary gland, breast fibroadenoma and breast cancer, as well as their relationship with the clinicopathological parameters of breast cancer. Methods: Expressions of HIC-1 and HMMR was examined by immunohistochemistry on 57 resected tissue samples taken at breast surgery: lobular hyperplasia 17 cases, fibroadenoma 20 cases and breast cancer 20 cases. The staining results were assessed semi-quantitatively, and were analyzed with the clinicopathological parameters of breast cancer. Results: ① HIC-1 was mo-derately positive in lobular hyperplasia and fibroadenoma tissue (average score 5.65), and was weakly positive in breast cancer tissue(average score 2.15). The difference in expression of HIC-1 between mammary benign lesions and breast cancer was significant (P<0.001). ② Expression of HMMR in mammary benign lesions was low (average score of fibroadenoma was 0.3, average score of lobular hyperplasia was 0), while the expression of HMMR in breast cancer was with an average score of 2.3 (P<0.001). ③ No obvious correlation was observed between protein expression of HIC-1 and HMMR and cli-nicopathological parameters of breast cancer. Conclusions: Expression of tumor suppression gene HIC-1 is significantly low and oncogene HMMR is relatively high in breast cancer. HIC-1 and the downstream gene HMMR regulated by HIC-1 may be involved in the development and progress of breast cancer.
[1] Fan L, Strasser-Weippl K, Li JJ, et al.Breast cancer in China[J]. Lancet Oncol,2014,15(7):e279-e289.
[2] Lu Y, Lin YZ, LaPushin R, et al. The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells[J]. Oncogene,1999,18(50):7034-7045.
[3] Fujii H, Biel MA, Zhou W, et al.Methylation of the HIC-1 candidate tumor suppressor gene in human breast cancer[J]. Oncogene,1998,16(16):2159-2164.
[4] Kanai Y, Hui AM, Sun L, et al.DNA hypermethylation at the D17S5 locus and reduced HIC-1 mRNA expression are associated with hepatocarcinogenesis[J]. Hepatology,1999,29(3):703-709.
[5] Nishida N, Nagasaka T, Nishimura T, et al.Aberrant methylation of multiple tumor suppressor genes in aging liver, chronic hepatitis, and hepatocellular carcinoma[J]. Hepatology,2008,47(3):908-918.
[6] Misra S, Hascall VC, Markwald RR, et al.Interactions between hyaluronan and its receptors(CD44, RHAMM) regulate the activities of inflammation and cancer[J]. Front Immunol,2015,6:201.
[7] 刘雷, 郭磊, 王志威, 等. 新型标志物HAB18G/CD147在大样本胃癌组织中的表达研究[J]. 诊断理论与实践,2012, 11(1):42-46.
[8] 赵峰, 张伟. HIC-1基因在肿瘤发生发展中的作用[J]. 外科理论与实践,2012,17(5):501-504.
[9] Wales MM, Biel MA, el Deiry W, et al. p53 activates expression of HIC-1, a new candidate tumour suppressor gene on 17p13.3[J]. Nat Med,1995,1(6):570-577.
[10] Boulay G, Malaquin N, Loison I, et al.Loss of hypermethylated in cancer 1 (HIC1) in breast cancer cells contributes to stress-induced migration and invasion through β-2 adrenergic receptor (ADRB2) misregulation[J]. J Biol Chem,2012,287(8):5379-5389.
[11] Nicoll G, Crichton DN, McDowell HE, et al. Expression of the hypermethylated in cancer gene (HIC-1) is associa-ted with good outcome in human breast cancer[J]. Br J Cancer,2001,85(12):1878-1882.
[12] 赵峰, 顾岩, 郭善禹, 等. HIC-1基因在乳腺癌的表达及其对细胞增殖和凋亡的影响[J]. 外科理论与实践,2013, 18(2):159-164.
[13] Zhao F, Pan S, Gu Y, et al.Small activating RNA restores the activity of the tumor suppressor HIC-1 on breast cancer[J]. PLoS One,2014,9(1):e86486.
[14] Entschladen F, Drell TL 4th, Lang K, et al. Tumour-cell migration, invasion, and metastasis: navigation by neurotransmitters[J]. Lancet Oncol,2004,5(4):254-258.
[15] Woodhouse EC, Chuaqui RF, Liotta LA.General mechanisms of metastasis[J]. Cancer,1997,80(8 Suppl):1529-1537.
[16] Wang C, Thor AD, Moore DH 2nd, et al. The overexpression of RHAMM, a hyaluronan-binding protein that regulates ras signaling, correlates with overexpression of mitogen-activated protein kinase and is a significant parameter in breast cancer progression[J]. Clin Cancer Res,1998,4(3):567-576.
[17] 程晓博, 范莹, 涂巍. CD168与乳腺癌预后的关系[J]. 辽宁大学学报,2013,40(2):185-188.
[18] 马万山, 李晓冰, 汪运山, 等. 胃癌患者原癌基因和抑癌基因的表达谱研究[J]. 肿瘤防治杂志,2002,9(4):379-381.