The human HECA interacts with cyclins and CDKs to antagonize Wnt-mediated proliferation and chemoresistance of head and neck cancer cells.

There is a growing evidence that the human homologue of the Drosophila headcase (HECA) plays an important role in human carcinogenesis. So far specific protein interaction partners and affected signaling pathways of HECA are still elusive. In a recent study we showed that HECA overexpression in oral squamous-cell carcinoma (OSCC) keratinocytes has tumor suppressive effects resulting in a recuperation of cell cycle control concerning the entry and progression of S-phase, G2- and M-phase. Currently, quantitative RT-PCR and immunohistochemical analysis of primary tumor tissue from OSCC patients demonstrate that HECA expression is markedly decreased compared to normal control patients with abundant HECA expression. Additionally, there is nearly no HECA expression in OSCC metastases. Here, we show that HECA expression is negatively controlled by the Wnt-pathway and TCF4, a Wnt related transcription factor, binds to the HECA promoter. Furthermore, immunocytochemistry reveals colocalization of HECA with the cyclin dependent kinase CDK9. Immunoprecipitation experiments and proximity ligation assays further reveal an interaction of HECA with CDK2, CDK9, Cyclin A and Cyclin K, a direct transcriptional target of the p53 tumor suppressor. Silencing HECA in OSCC cell lines leads to a significant increase of cell division and a markedly increased resistance against the chemotherapeutic cisplatin. On the contrary, HECA overexpressing OSCC cell lines show decreased resistance of OSCC cells against cisplatin. Therefore, HECA could be considered as future therapeutic agent against Wnt-dependent tumor progression.

Dowejko A ，Bauer R ，Bauer K ，Müller-Richter UD ，Reichert TE ... -  《-》

Up-regulation of survivin in oral squamous cell carcinoma correlates with poor prognosis and chemoresistance.

Survivin, a key member of the inhibitor of apoptosis protein family, has been reported to be capable of regulating both cellular proliferation and apoptotic cell death. This protein is found to be overexpressed in many human cancers. The aim of this study was to evaluate the prognostic significance of survivin mRNA expression in oral squamous cell carcinoma (OSCC) and to analyze its correlation with chemoresistance. Reverse-transcription polymerase chain reaction assay was performed to detect the expression of survivin mRNA in OSCC cell lines or tissue samples. Immunohistochemistry was performed to detect the expression of survivin protein in OSCC tissues or corresponding nontumor tissues. Then the correlation between survivin mRNA expression and clinicopathologic features or prognosis of OSCC patients was analyzed. Small interfering RNA technology was used to down-regulate the expression of the survivin gene in the OSCC cell line. Methylthiazol tetrazolium and flow cytometric assays were performed to detect proliferation and apoptosis of the OSCC cell line (HSC-3). Furthermore, the effect of small interfering RNA (siRNA) targeting survivin on the sensitivity of OSCC cells to chemotherapeutic agents (cisplatin and 5-fluorouracil [5-FU]) was determined. Results showed that the levels of survivin mRNA expression were significantly higher in OSCC cells or tissues than those in normal human oral keratinocyte or corresponding noncancerous tissues. The immunostaining of survivin protein was significantly stronger in OSCC tissues than in corresponding nontumor tissues. Moreover, high survivin mRNA expression was correlated with poorer tumor differentiation, higher clinical stage, and the presence of lymph node metastasis (P < .05). Multivariate analysis showed that the status of survivin mRNA could be an independent prognostic factor for OSCC patients (hazard ratio 2.71, 95% confidence interval 1.46-5.10; P = .012). In addition, siRNA-mediated survivin down-regulation could significantly inhibit proliferation and induce apoptosis of OSCC cells. Suvivin down-regulation could also significantly enhance chemosensitivity of OSCC cells, which was associated with apoptosis enhancement. Thus, the status of survivin mRNA expression was a potential prognostic factor for OSCC patients, and siRNA-mediated survivin down-regulation could become a novel strategy for chemosensitization of human OSCCs.

Su L ，Wang Y ，Xiao M ，Lin Y ，Yu L ... -  《-》

The human homolog of the Drosophila headcase protein slows down cell division of head and neck cancer cells.

Dowejko A ，Bauer RJ ，Müller-Richter UD ，Reichert TE ... -  《-》

Daxx and TCF4 interaction links to oral squamous cell carcinoma growth by promoting cell cycle progression via induction of cyclin D1 expression.

Lin GJ ，Huang YS ，Lin CK ，Huang SH ，Shih HM ，Sytwu HK ，Chen YW ... -  《-》

The Human Homolog of Drosophila Headcase Acts as a Tumor Suppressor through Its Blocking Effect on the Cell Cycle in Hepatocellular Carcinoma.

Wang J ，Gong L ，Zhu SJ ，Zhu Q ，Yao L ，Han XJ ，Zhang JR ，Li YH ，Zhang W ... -  《-》