Lam-Himlin Dora M, Daniels Jason A, Gayyed Mariana F, Dong Jixin, Maitra Anirban, Pan Duojia, Montgomery Elizabeth A, Anders Robert A
Department of Pathology, University of Maryland, Baltimore, MD 21201, USA.
Int J Gastrointest Cancer. 2006;37(4):103-9. doi: 10.1007/s12029-007-0010-8.
The Hippo (Hpo) pathway is highly conserved in humans and was originally uncovered in Drosophila as a potent regulator of inhibiting cell growth and promoting apoptosis. The Hippo pathway consists of a tumor suppressor kinase cascade that negatively regulates growth and results in inactivation of a transcriptional co-activator, Yorkie (yki). The human ortholog of Yki, the yes-associated protein (YAP), has a 31% sequence identity and similar biologic activity. The potential role of YAP in tumorigenesis was also reported in a murine genetic screen which identified a genomic amplification of YAP in hepatocellular carcinoma.
Given this pathway's critical control of cell growth, survival, proliferation, and amplification in malignancy, we wanted to explore the possible role of the Hippo pathway in human esophageal and gastric tumorigenesis.
The expression of YAP was evaluated with immunolabeling of esophageal and gastric tissue microarrays from 169 patients, with nondysplastic, dysplastic, and malignant foci represented. Cytoplasmic and nuclear staining were scored as 0 = none, 1 < 10%, 2 = 10-50%, and 3 > 50% for the nonneoplastic, dysplastic, and malignant epithelium. Multiple scores were averaged for each patient. Expression of YAP could be seen in the proliferating compartments of nonneoplastic tissue.
Compared to nonneoplastic epithelium, there was a significant increase in YAP cytoplasmic and nuclear localization in high-grade dysplastic epithelium and adenocarcinoma of the esophagus. There was also a significant increase in YAP cytoplasmic and nuclear staining of gastric carcinoma and metastatic gastric disease compared to nonneoplastic gastric tissue.
YAP expression in the cytoplasm and nucleus is significantly increased in high-grade dysplasia and adenocarcinoma of the esophagus as well as gastric adenocarcinoma and metastatic gastric disease, suggesting a role for this recently uncovered pathway in esophageal and gastric epithelial tumorigenesis.
河马（Hpo）通路在人类中高度保守，最初在果蝇中被发现是抑制细胞生长和促进细胞凋亡的有效调节因子。河马通路由一个肿瘤抑制激酶级联组成，该级联对生长起负调节作用，并导致转录共激活因子Yorkie（yki）失活。Yki在人类中的同源物，即Yes相关蛋白（YAP），具有31%的序列同一性和相似的生物学活性。在一项小鼠基因筛选中也报道了YAP在肿瘤发生中的潜在作用，该筛选确定了肝细胞癌中YAP的基因组扩增。
鉴于该通路对细胞生长、存活、增殖以及恶性肿瘤中的扩增具有关键控制作用，我们想要探究河马通路在人类食管和胃肿瘤发生中的可能作用。
通过对169例患者的食管和胃组织微阵列进行免疫标记来评估YAP的表达，这些微阵列代表了非发育异常、发育异常和恶性病灶。对于非肿瘤性、发育异常和恶性上皮，细胞质和细胞核染色评分分别为0 = 无，1 < 10%，2 = 10 - 50%，3 > 50%。对每位患者的多个评分进行平均。YAP的表达可见于非肿瘤组织的增殖区室。
与非肿瘤性上皮相比，食管高级别发育异常上皮和腺癌中YAP的细胞质和细胞核定位显著增加。与非肿瘤性胃组织相比，胃癌和转移性胃疾病中YAP的细胞质和细胞核染色也显著增加。
YAP在细胞质和细胞核中的表达在食管高级别发育异常和腺癌以及胃腺癌和转移性胃疾病中显著增加，表明这一最近发现的通路在食管和胃上皮肿瘤发生中发挥作用。
