ROLE OF RUNX3 IN HEAD AND NECK CANCER

Cumulative evidences show that Runt-related transcription factor 3 (RUNX3) has a tumor suppressive role in various cancers. In particular, RUNX3 appears to be an important component of the transforming growth factor-beta (TGF-ß)-induced tumor suppression pathway. Contrary to reports on this tumor suppressive role of RUNX3, RUNX3 can also function as an oncogene when overexpressed. Recently, we found that RUNX3 overexpression was frequently observed and was well correlated with malignant behaviors in head and neck cancer, which is one of the most common types of human cancer. Moreover, it has been revealed that RUNX3 overexpression promoted cell growth and inhibited apoptosis in head and neck cancer cells. This review introduces the oncogenic role of RUNX3 in certain types of cancer including head and neck cancer

Aurora-A controls pre-replicative complex assembly and DNA replication by stabilizing geminin in mitosis

Geminin, an essential factor for DNA replication, directly binds to the licensing factor Cdt1 and inhibits pre-replicative complex formation to prevent re-replication. In G1, geminin levels are controlled by the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase complex, which targets geminin for proteasomal degradation to allow pre-replicative complex formation. Conversely, from S to G2, geminin is stabilized due to APC/C ubiquitin ligase complex inhibition, ensuring the inhibition of pre-replicative complex formation. However, mitotic regulation of geminin has hitherto not been described. Here we show that Aurora-A phosphorylates geminin on Thr25 during M phase, and this event induces geminin stabilization by preventing its APC/C ubiquitin ligase complex-mediated degradation during mitosis. In turn, stabilized geminin inhibits SCFSkp2-mediated degradation of Cdt1 to ensure pre-replicative complex formation in the ensuing S phase. The Aurora-A–geminin–Cdt1 axis therefore represents a critical regulator of proper DNA replication

IFITM1 Promotes Invasion of HNSCC Cells

Purpose: Head and neck squamous cell carcinoma (HNSCC), one of the most common types of human cancer, show persistent invasion that frequently leads to local recurrence and distant lymphatic metastasis. However, molecular mechanisms associated with invasion of HNSCC remain poorly understood. We identified Interferon-induced transmembrane protein 1 (IFITM1) as a candidate gene for promoting the invasion of HNSCC by comparing the gene expression profiles between parent and a highly invasive clone. Therefore, we examined the role of IFITM1 in the invasion of HNSCC. Experimental Design: IFITM1 expression was examined in HNSCC cell lines and cases by RT-PCR and immunohistochemistry. IFITM1 overexpressing and knockdown cells were generated, and the invasiveness of these cells was examined by in vitro invasion assay. Gene expression profiling of HNSCC cells overexpressing IFITM1 versus control cells was examined by microarray. Results: HNSCC cells expressed IFITM1 mRNA at higher levels, while normal cells did not express. By immunohistochemistry, IFITM1 expression was observed in early invasive HNSCC and invasive HNSCC. Interestingly, IFITM1 was expressed at the invasive front of early invasive HNSCC, and higher expression of IFITM1 was found in invasive HNSCC. In fact, IFITM1 overexpression promoted and IFITM1 knockdown suppressed the invasion of HNSCC cells in vitro. Gene expression profiling of HNSCC cells overexpressing IFITM1 versus control cells revealed that several genes including matrix metalloproteinase were up-regulated in IFITM1 overexpressing cells. Conclusion: Our findings suggest that IFITM1 plays an important role for the invasion at the early stage of HNSCC progression, and that IFITM1 can be a therapeutic target for HNSCC

RUNX3 Has an Oncogenic Role

Background: Runt-related transcription factor 3 (RUNX3) is a tumor suppressor of cancer and appears to be an important component of the transforming growth factor-beta (TGF-ß)-induced tumor suppression pathway. Surprisingly, we found that RUNX3 expression level in head and neck squamous cell carcinoma (HNSCC) tissues, which is one of the most common types of human cancer, was higher than that in normal tissues by a previously published microarray dataset in our preliminary study. Therefore, here we examined the oncogenic role of RUNX3 in HNSCC. Principal Findings: Frequent RUNX3 expression and its correlation with malignant behavior were observed in HNSCC. Ectopic RUNX3 overexpression promoted cell growth and inhibited serum starvation-induced apoptosis and chemotherapeutic drug induced apoptosis in HNSCC cells. These findings were confirmed by RUNX3 knockdown. Moreover, RUNX3 overexpression enhanced tumorsphere formation. RUNX3 expression level was well correlated with the methylation status in HNSCC cells. Moreover, RUNX3 expression was low due to the methylation of its promoter in normal oral epithelial cells. Conclusions/Significance: Our findings suggest that i) RUNX3 has an oncogenic role in HNSCC, ii) RUNX3 expression observed in HNSCC may be caused in part by demethylation during cancer development, and iii) RUNX3 expression can be a useful marker for predicting malignant behavior and the effect of chemotherapeutic drugs in HNSCC

RUNX3 Has an Oncogenic Role in Head and Neck Cancer

Background: Runt-related transcription factor 3 (RUNX3) is a tumor suppressor of cancer and appears to be an important component of the transforming growth factor-beta (TGF-ß)-induced tumor suppression pathway. Surprisingly, we found that RUNX3 expression level in head and neck squamous cell carcinoma (HNSCC) tissues, which is one of the most common types of human cancer, was higher than that in normal tissues by a previously published microarray dataset in our preliminary study. Therefore, here we examined the oncogenic role of RUNX3 in HNSCC. Principal Findings: Frequent RUNX3 expression and its correlation with malignant behavior were observed in HNSCC. Ectopic RUNX3 overexpression promoted cell growth and inhibited serum starvation-induced apoptosis and chemotherapeutic drug induced apoptosis in HNSCC cells. These findings were confirmed by RUNX3 knockdown. Moreover, RUNX3 overexpression enhanced tumorsphere formation. RUNX3 expression level was well correlated with the methylation status in HNSCC cells. Moreover, RUNX3 expression was low due to the methylation of its promoter in normal oral epithelial cells. Conclusions/Significance: Our findings suggest that i) RUNX3 has an oncogenic role in HNSCC, ii) RUNX3 expression observed in HNSCC may be caused in part by demethylation during cancer development, and iii) RUNX3 expression can b

Ameloblastin regulates osteogenic differentiation

Ameloblastin, the most abundant non-amelogenin enamel matrix protein, plays a role in ameloblast differentiation. Here we found that ameloblastin was expressed in osteosarcoma cells; to explore the potential functions of ameloblastin in osteoblasts, we investigated whether this protein is involved in osteogenic differentiation and bone formation on the premise that CD63, a member of the transmembrane-4 glycoprotein superfamily, interacts with integrins in the presence of ameloblastin. Ameloblastin bound to CD63 and promoted CD63 binding to integrin β1. The interaction between CD63 and integrin β1 induced Src kinase inactivation via the binding of CD63 to Src. The reduction of Src activity and osteogenic differentiation mediated by ameloblastin was abrogated by treatment with anti-CD63 antibody and overexpression of constitutive active Src, respectively. Moreover, amelobastin upregulated the formation of stress-fibre and focal adhesions and downregulated cell migration in association with RhoA regulation via Src activity. Therefore, our results suggest that ameloblastin is expressed in osteoblasts and functions as a promoting factor for osteogenic differentiation via a novel pathway through the interaction between CD63 and integrin β1

Periostin Promotes Tumor Lymphangiogenesis

Background: Metastasis to regional lymph nodes via lymphatic vessels plays a key role in cancer progression. Tumor lymphangiogenesis is known to promote lymphatic metastasis, and vascular endothelial growth factor C (VEGF-C) is a critical activator of tumor lymphangiogenesis during the process of metastasis. We previously identified periostin as an invasion- and angiogenesis-promoting factor in head and neck squamous cell carcinoma (HNSCC). In this study, we discovered a novel role for periostin in tumor lymphangiogenesis. Methods and Findings: Periostin overexpression upregulated VEGF-C mRNA expression in HNSCC cells. By using conditioned media from periostin-overexpressing HNSCC cells, we examined tube formation of lymphatic endothelial cells. Conditioned media from periostin-overexpressing cells promoted tube formation. To know the correlation between periostin and VEGF-C, we compared Periostin expression with VEGF-C expression in 54 HNSCC cases by immunohistochemistry. Periostin expression was correlated well with VEGF-C expression in HNSCC cases. Moreover, correlation between periostin and VEGF-C secretion was observed in serum from HNSCC patients. Interestingly, periostin itself promoted tube formation of lymphatic endothelial cells independently of VEGF-C. Periostin-promoted lymphangiogenesis was mediated by Src and Akt activity. Indeed possible correlation between periostin and lymphatic status in periostin-overexpressing xenograft tumors and HNSCC cases was observed. Conclusions: Our findings suggest that periostin itself as well as periostin-induced upregulation of VEGF-C may promote lymphangiogenesis. We suggest that periostin may be a marker for prediction of malignant behaviors in HNSCC and a potential target for future therapeutic intervention to obstruct tumoral lymphatic invasion and lymphangiogenesis in HNSCC patients

MMP-10/Stromelysin-2 Promotes Invasion of Head and Neck Cancer

Background: Periostin, IFN-induced transmembrane protein 1 (IFITM1) and Wingless-type MMTV integration site family, member 5B (Wnt-5b) were previously identified as the invasion promoted genes of head and neck squamous cell carcinoma(HNSCC) by comparing the gene expression profiles between parent and a highly invasive clone. We have previously reported that Periostin and IFITM1 promoted the invasion of HNSCC cells. Here we demonstrated that Wnt-5b overexpression promoted the invasion of HNSCC cells. Moreover, stromelysin-2 (matrix metalloproteinase-10; MMP-10) was identified as a common up-regulated gene among Periostin, IFITM1 and Wnt-5b overexpressing HNSCC cells by using microarray data sets. In this study, we investigated the roles of MMP-10 in the invasion of HNSCC. Methods and Findings: We examined the expression of MMP-10 in HNSCC cases by immunohistochemistry. High expression of MMP-10 was frequently observed and was significantly correlated with the invasiveness and metastasis in HNSCC cases. Next, we examined the roles of MMP-10 in the invasion of HNSCC cells in vitro. Ectopic overexpression of MMP-10 promoted the invasion of HNSCC cells, and knockdown of MMP-10 suppressed the invasion of HNSCC cells. Moreover, MMP-10 knockdown suppressed Periostin and Wnt-5b-promoted invasion. Interestingly, MMP-10 overexpression induced the decreased p38 activity and MMP-10 knockdown induced the increased p38 activity. In addition, treatment with a p38 inhibitor SB203580 in HNSCC cells inhibited the invasion. Conclusions: These results suggest that MMP-10 plays an important role in the invasion and metastasis of HNSCC, and that invasion driven by MMP-10 is partially associated with p38 MAPK inhibition. We suggest that MMP-10 can be used as a marker for prediction of metastasis in HNSCC

Selective Effects of Emi1 Depletion in Cancer

Background: To improve the effectiveness of chemo- and radiotherapy only in cancer tissue is important for avoiding side effects. Results: Emi1 depletion enhanced the sensitivity of anticancer reagents and X-ray irradiation in cancer cells. Conclusion: Emi1 siRNA would be a useful new modality for enhancing the effect of chemo- and radiotherapy in various tumors. Significance: This work provides new insights regarding synergistic effect of Emi1 knockdown in combination therapies