92304

SCGB3A1

HIN-1|HIN1|LU105|PnSP-2|UGRP2;secretoglobin, family 3A, member 1;SCGB3A1;secretoglobin, family 3A, member 1

cytokine HIN-1|cytokine high in normal-1|high in normal 1|pneumo secretory protein 2|secretoglobin family 3A member 1|uteroglobin-related protein 2

5q35-qter

protein-coding

Count: 1; Generif

PURPOSE: Radiotherapy is the standard adjuvant treatment for oral squamous cell carcinoma (OSCC). The Ras/PI3K/AKT pathway is the major mechanism associated with radioresistance. To evaluate the potential significance on the outcome of radiotherapy in OSCC of the Ras/PI3K/AKT pathway with respect to methylation of negative regulators, we examined the methylation status of genes known to be involved in Ras/PI3K/AKT pathway and aberrantly methylated in human cancers together with the mutation status of K-ras/H-ras. EXPERIMENTAL DESIGN: PCR--denaturing high-performance liquid chromatography was used to examine the methylation status of the RASSF1A, RASSF2A, PTEN, and HIN-1 genes, and PCR-RFLP was used to determine the mutation status of K-ras/H-ras in 482 OSCCs. Associations between mutation, methylation, clinicopathologic parameters, and outcome were evaluated. RESULTS: The frequencies of K-ras/H-ras mutation and promoter methylation of the RASSF1A, RASSF2A, PTEN, and HIN-1 genes were 6.6%, 22.4%, 27.8%, 1.2%, and 7.3%, respectively. A combination of RASSF1A and RASSF2A methylation was found to be significantly associated with poor disease-free survival (DFS). Furthermore, a gene dosage effect of the activated Ras/PI3K/AKT signal on DFS was observed in patients treated with radiotherapy after surgery but not in patients treated with surgery alone. The Ras/PI3K/AKT pathway was activated in 140 primary OSCCs among 286 patients treated with radiotherapy after surgery and methylation of RASSF1A/RASSF2A (75.7%) was the most common mechanism. CONCLUSION: Our study indicates that epigenetic silencing of tumor suppressor genes involved in the Ras/PI3K/AKT pathway plays an important role in OSCC radioresistance and this provides a rationale for exploring novel treatment strategies.

The HIN-1 gene encoding a small, secreted protein is silenced due to methylation in a substantial fraction of breast, prostate, lung, and pancreatic carcinomas, suggesting a potential tumor suppressor function. The receptor of HIN-1 is unknown, but ligand-binding studies indicate the presence of high-affinity cell surface HIN-1 binding on epithelial cells. Here, we report that HIN-1 is a potent inhibitor of anchorage-dependent and anchorage-independent cell growth, cell migration, and invasion. expression of HIN-1 in synchronized cells inhibits cell cycle reentry and the phosphorylation of the retinoblastoma protein (Rb), whereas in exponentially growing cells, HIN-1 induces apoptosis without apparent cell cycle arrest and effect on Rb phosphorylation. Investigation of multiple signaling pathways revealed that mitogen-induced phosphorylation and activation of AKT are inhibited in HIN-1-expressing cells. In addition, expression of constitutively activate AKT abrogates HIN-1-mediated growth arrest. Taken together, these studies provide further evidence that HIN-1 possesses tumor suppressor functions, and that these activities may be mediated through the AKT signaling pathway.