The Hpo pathway was originally identified in Drosophila as a potent regulator of inhibition of cell growth and promotion of apoptosis. The pathway consists of a tumor suppressor kinase cascade which negatively regulates growth and results in inactivation of a transcriptional co-activator, Yorkie (Yki)[8
]. The human ortholog of Yki, YAP, has a 31% sequence homology and similar biologic activity. YAP is a 65 kDa phosphoprotein which is rich in proline. In biological conditions, YAP is phosphorylated by the Hpo signaling pathway, and is highly conserved with other components of this pathway, regulating the balance between cell proliferation and apoptosis to maintain the steady-state of the cellular environment[2,9,10
]. Dysregulation of any factor(s) in this pathway can lead to tumorigenesis. Overholtzer et al[3
] introduced the YAP gene by retroviral infection into the immortalized, but non-tumorigenic, human mammary epithelial cell line MCF10A and found that overexpression of YAP induced epithelial-to-mesenchymal transition, suppression of apoptosis, growth factor-independent proliferation, and anchorage-independent growth in soft agar, which suggests that YAP contributes to malignant transformation in cancers, and supports the potential significance of this pathway in human cancer.
Zhao et al[2
] evaluated YAP expression in 115 cases of human hepatocellular carcinoma (HCC) samples by IHC staining of tissue microarrays. Among the 115 cases of human HCC samples examined, 54% showed strong YAP staining, while 95% of normal liver tissue samples (40 out of 42 cases) showed very weak staining, indicating a significant difference in YAP levels between normal and cancerous tissues. Similar observations were made in prostate cancer tissues. Up to now, we have found only one report on the expression and role of YAP expression in gastric carcinoma, where YAP expression in 78 normal gastric mucosa was 14%, while in 55 gastric carcinomas and 92 gastric metastatic disease the expression was 30% and 35% respectively, significantly higher than that in normal gastric mucosa[11
]. Our IHC investigation found that the expression of YAP in DYS and gastric carcinoma was significantly higher than in normal gastric mucosa, suggesting that an abnormality of the Hpo pathway leads to overexpression of YAP, resulting in malignant transformation of the gastric mucosa. We speculate that YAP may play an important role as a tumorigenic factor and early gastric tumorigenic molecule during gastric carcinogenesis.
Survivin is a new member of the IAP family, and has been implicated to have a role in protection from apoptosis and regulation of mitosis[12
]. The survivin gene has been located on the 17q25 chromosome, encoding a 16.5 kDa protein. Survivin is characterized by a unique structure with a single BIR on the N terminal and an α-helix structure on the C terminal; the BIR structure is thought to play a role during anti-apoptosis, while the helix structure may participate in the microtubule binding structure[13,14
]. Data from a large analysis of human transcripts revealed survivin as the fourth most highly expressed protein in human cancer tissue compared with normal tissue[15–18
]. Xiao et al[19
] found that the positive rates of survivin expression in tumors with metastases (in lymph node metastasis 86.2%, liver metastasis 100% and ovarian metastasis 100%) were significantly higher than that in tumors without metastasis (64.3%). Our data indicated that the positive rates of survivin in IM, atypical hyperplasia and gastric carcinoma were significantly higher than that in normal gastric mucosa. The expression level gradually increased from well differentiated adenocarcinoma, through moderately differentiated adenocarcinoma to poorly differentiated adenocarcinoma, with significant Rank correlation. The positive rate of survivin in gastric carcinoma of the diffused type was significantly higher than that in the intestinal type. In gastric carcinoma with lymph node metastasis, the positive rate of survivin was significantly higher than that in the group without lymph node metastasis, indicating that survivin may be involved in the occurrence, development and lymph node metastasis of gastric carcinoma. Survivin can act as a prognostic and predictive indicator for gastric carcinoma patients.
Dong et al[7
] used microarray analysis to identify YAP-induced genes in murine livers. Selected genes from the microarray analysis were validated by real-time quantitative polymerase chain reaction analysis. YAP induced the transcription of many genes which are normally associated with hepatocyte proliferation, such as Ki67, c-myc, SOX4, H19, and AFP. It also induced the expression of several negative regulators of apoptosis, such as the IAP family members BIRC5/survivin and BIRC2/cIAP1, and the BCL2 family gene MCL1. Of note is the massive induction (30-fold) of BIRC5/survivin. To determine whether cIAP1 and YAP might cooperate during tumorigenesis, p53-/-
, myc liver progenitor cells were infected with either YAP and control vector or YAP plus cIAP1 and assayed for their ability to form tumors in vivo
. Tumors arising from p53-/-
, myc hepatoblasts coexpressing cIAP1 and YAP grew faster than those expressing either oncogene alone, suggesting that they may collaborate to contribute to tumorigenesis and progression[20
Our investigation found that the expression of YAP and survivin in gastric carcinoma were positively correlated, and we speculate that YAP may induce a high expression of cell proliferation-related factors and apoptotic inhibitors, such as Ki67, cIAP1 and survivin. Survivin may participate in gastric carcinogenesis, progression and metastasis by inhibiting apoptosis of gastric carcinoma and regulating cellular mitosis. Whether YAP and survivin collaborate to contribute to gastric carcinogenesis and progression require further study.
Previous reports have found that YAP was an activator of cell death in mammalian cells. YAP was shown to activate apoptosis in response to DNA damage by interacting with p73 in several cancer cell lines[21,22
]. This is in direct contrast to the results of our investigation and other previous reports. The roles of YAP in biological and pathological conditions remain to be clearly defined.