Ralhan R, Mathew R, Arora S, Bahl R, Shukla N K, Mathur M
Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi.
J Cancer Res Clin Oncol. 2000 Nov;126(11):655-60. doi: 10.1007/s004320000147.
Alterations in the cell cycle regulatory p16INK4a/Cyclin D1/pRb pathway play a pivotal role in tumorigenesis. Knowledge of alterations in the tumor suppressor protein pRb and its negative regulator, p16CDKN2/MTS1/INK4a in esophageal squamous cell carcinoma (ESCC) from the Indian subcontinent is meager. To gain insight into the mechanisms underlying tumorigenesis and to search for diagnostic molecular markers for ESCC, we analyzed the expression of p16INK4a and pRb in ESCCs in the Indian population.
Immunohistochemical analysis of pRb and p16INK4a proteins was carried out in paraffin-embedded sections from 61 surgically resected ESCCs and matched normal tissues, and the results correlated with clinicopathological parameters using chi square and Fisher's exact tests. Dual immunohistochemical analysis has been carried out to demonstrate the concomitant loss of expression of p16INK4a and pRb.
Fifty-nine of 61 (97%) cases showed aberration(s) in either or both of these proteins confirming their critical role in esophageal tumorigenesis. Loss of pRb was observed in 51 of the 61 (84%) and loss of p16INK4a was observed in 35 of 61 (57%) cases. Loss of pRb showed significant association with dedifferentiation of the tumor (P = 0.004). p16-/pRb-, and p16+/pRb- phenotypes were significantly associated with nodal metastasis (P = 0.017 and 0.027, respectively), while p16-/pRb+ phenotype was associated with dedifferentiation of the tumor (P = 0.012).
pRb/p16INK4a pathway plays a critical role in esophageal tumorigenesis in the Indian population. The dual hits (concomitant loss) of pRb and p16INK4a expression suggest that these two components are not mutually exclusive, and can both be altered in a significant proportion of primary ESCCs serving as putative diagnostic markers for esophageal cancer. However, the impact of dual hit on tumor behavior and disease prognosis remains to be determined.
细胞周期调节蛋白p16INK4a/细胞周期蛋白D1/pRb通路的改变在肿瘤发生中起关键作用。关于印度次大陆食管鳞状细胞癌（ESCC）中肿瘤抑制蛋白pRb及其负调节因子p16CDKN2/MTS1/INK4a改变的知识却很匮乏。为深入了解肿瘤发生的潜在机制并寻找ESCC的诊断分子标志物，我们分析了印度人群ESCC中p16INK4a和pRb的表达情况。
对61例手术切除的ESCC及其配对正常组织的石蜡包埋切片进行pRb和p16INK4a蛋白的免疫组织化学分析，结果采用卡方检验和Fisher精确检验与临床病理参数进行相关性分析。进行双重免疫组织化学分析以证明p16INK4a和pRb表达的同时缺失。
61例中有59例（97%）显示这两种蛋白中的一种或两种出现异常，证实了它们在食管肿瘤发生中的关键作用。61例中有51例（84%）观察到pRb缺失，61例中有35例（57%）观察到p16INK4a缺失。pRb缺失与肿瘤去分化显著相关（P = 0.004）。p16-/pRb-和p16+/pRb-表型与淋巴结转移显著相关（分别为P = 0.017和0.027），而p16-/pRb+表型与肿瘤去分化相关（P = 0.012）。
pRb/p16INK4a通路在印度人群的食管肿瘤发生中起关键作用。pRb和p16INK4a表达的双重打击（同时缺失）表明这两个成分并非相互排斥，并且在相当比例的原发性ESCC中均可改变，可作为食管癌的潜在诊断标志物。然而，双重打击对肿瘤行为和疾病预后的影响仍有待确定。
