Role of ING4 in human melanoma cell migration, invasion and patient survival
Jun Li1, Magdalena Martinka, Gang Li
1Department of Dermatology and Skin Science, Jack Bell Research Centre, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada.
Abstract:
Inhibitor of growth (ING) 4 has been reported as a tumor suppressor and shown to diminish colony-forming efficiency, induce p53-dependent apoptosis and arrest cell cycle at G(2)-M phase. In this study, we investigated the role of ING4 in human melanoma pathogenesis. Using the tissue microarray technology, we found that ING4 expression is significantly decreased in malignant melanoma compared with dysplastic nevi (P < 0.0001, chi(2) test) and reduced ING4 staining is associated with melanoma thickness, ulceration (P = 0.034 and 0.002, respectively, chi(2) test) as well as poor overall and disease-specific 5-year survival of primary melanoma patients (P = 0.0002 and 0.001, respectively, chi(2) test). Cox regression analysis revealed that reduced ING4 staining is an independent factor for the poor prognosis of patients with primary melanomas. Furthermore, we found that overexpression of ING4 suppressed cell migration by 63% and inhibited the activity of Ras homolog gene family member A (RhoA) small GTPase protein and Rho-associated kinase (ROCK)-mediated formation of stress fiber in melanoma cells. Moreover, our data showed that overexpression of ING4 inhibited melanoma cell invasion by 43% compared with the control (P = 0.006, t-test) and ING4-overexpressing melanoma cells showed significantly reduced activity of matrix metalloproteinase (MMP)-2 and MMP-9. Taken together, this study highlights the importance of ING4 in melanoma pathogenesis and ING4 may serve as a promising prognostic marker and a potential therapeutic target for human melanoma.
Insights
Inhibitor of growth 4 (ING4) is decreased in melanoma, correlating with thicker tumors and poorer survival. Overexpressing ING4 suppresses melanoma cell migration, invasion, and metastasis, suggesting it
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Inhibitor of growth 4 (ING4) is a known tumor suppressor involved in apoptosis and cell cycle arrest.
- Its role in human melanoma pathogenesis requires further investigation.
Purpose of the Study:
- To investigate the role of ING4 in human melanoma.
- To evaluate ING4 as a prognostic marker and potential therapeutic target.
Main Methods:
- Tissue microarray analysis of ING4 expression in melanoma and dysplastic nevi.
- Correlation analysis of ING4 expression with clinical parameters and patient survival.
- In vitro studies assessing the effects of ING4 overexpression on melanoma cell migration, invasion, and matrix metalloproteinase activity.
Main Results:
- ING4 expression is significantly decreased in malignant melanoma compared to dysplastic nevi.
- Reduced ING4 expression correlates with increased melanoma thickness, ulceration, and poorer patient survival.
- Overexpression of ING4 inhibits melanoma cell migration (63%), invasion (43%), and reduces the activity of MMP-2 and MMP-9.
Conclusions:
- ING4 downregulation is associated with melanoma progression and poor prognosis.
- ING4 acts as a suppressor of melanoma cell migration and invasion.
- ING4 represents a potential prognostic biomarker and therapeutic target for melanoma.
