Cheah Phaik-Leng, Looi Lai-Meng, Mun Kein-Seong, Abdoul Rahman Nazarina, Teoh Kean-Hooi
Department of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
Malays J Pathol. 2011 Dec;33(2):83-7.
On integration into the host cervical keratinocyte genome, human papillomavirus (HPV) E7 protein binds pRB,releasing E2F from normally incompetent pRB-E2F complexes and allowing propagation of G1-S transition by the E2F. p16(INK4a), a tumour suppressor protein, increases in reflex response to counter this. 29 histologically re-confirmed low-grade squamous intraepithelial lesions (LSIL), 27 high-grade squamous intraepithelial lesions (HSIL) and 30 invasive cervical squamous carcinoma (SCC) were immunohistochemically stained for p16(INK4a) expression using the CINtec Histology Kit (REF 9511, mtm laboratories AG, Heidelberg, Germany) to re-affirm the notion that integration of HPV occurs predominantly in SCC and possibly HSIL and less in LSIL and normal squamous epithelium (NSqE). Implicit was also the attempt to understand the role of E2F, as indicated by p16(INK4a), in evolution of SCC from HSIL. No ethnic predilection was noted for LSIL, HSIL or SCC. Patients with SCC were significantly older by about 14-years compared with HSIL (p < 0.05) while there was no significant age difference between HSIL and LSIL. p16(INK4a) expression was significantly increased (p < 0.05) in both HSIL (88.9%) and SCC (83.3%) compared with LSIL (3.4%) and NSqE (0%); the NSqE being normal squamous epithelium noted in 17 of the LSIL, 19 HSIL and 5 SCC. From these findings there is suggestion that fundamental upstream events viz HPV integration, E7 upregulation followed by E2F activation occurs at point of transformation to HSIL and continues unrelentingly for another one to two decades before hitherto unclear factors convert a non-invasive lesion into an overtly invasive malignant counterpart. Interestingly, the occurrence of HSIL and LSIL in almost the same age group could mean that alteration from episomal to integrated form of HPV may not incur a prolonged incubation period, unlike from HSIL to SCC.
人乳头瘤病毒（HPV）E7蛋白整合入宿主宫颈角质形成细胞基因组后，会与视网膜母细胞瘤蛋白（pRB）结合，将E2F从通常无活性的pRB - E2F复合物中释放出来，使E2F能够促进G1 - S期转换。肿瘤抑制蛋白p16（INK4a）会通过反馈反应增加以对抗这种情况。使用CINtec组织学检测试剂盒（产品编号9511，mtm laboratories AG，德国海德堡）对29例经组织学再次确认的低级别鳞状上皮内病变（LSIL）、27例高级别鳞状上皮内病变（HSIL）和30例浸润性宫颈鳞癌（SCC）进行p16（INK4a）表达的免疫组化染色，以再次证实HPV整合主要发生在SCC中，可能也存在于HSIL中，而在LSIL和正常鳞状上皮（NSqE）中较少见的观点。这其中还隐含着试图了解如p16（INK4a）所示的E2F在HSIL向SCC演变过程中的作用。未发现LSIL、HSIL或SCC存在种族偏好。与HSIL患者相比，SCC患者年龄显著大14岁左右（p < 0.05），而HSIL和LSIL之间无显著年龄差异。与LSIL（3.4%）和NSqE（0%）相比，HSIL（88.9%）和SCC（83.3%）中的p16（INK4a）表达显著增加（p < 0.05）；NSqE是在17例LSIL、19例HSIL和5例SCC中发现的正常鳞状上皮。从这些发现可以推测，基本的上游事件，即HPV整合、E7上调继而E2F激活，发生在向HSIL转变之时，并在接下来的一到二十年中持续不断，直到一些尚不清楚的因素将非侵袭性病变转变为明显侵袭性的恶性病变。有趣的是，HSIL和LSIL几乎出现在相同年龄组，这可能意味着HPV从游离形式转变为整合形式可能不会像从HSIL到SCC那样导致较长的潜伏期。
