TGFβ1-Smad3-Jagged1-Notch1-Slug signaling pathway takes part in tumorigenesis and progress of tongue squamous cell carcinoma.

TGFβ1 and Smad3 play an important role in the process of EMT. TGFβ1 regulates the expression of Jagged1 by modulating Notch signaling. Jagged1 is related to tumor invasion, metastasis, chemotherapy resistance, and tumor immune escape. The aims of this study are to examine deregulation of TGFβ1-Smad3-Jagged1-Notch1-Slug signaling in TSCC and to investigate its roles in TSCC progression. Notch1, Smad3, Jagged1 and Slug proteins and mRNA expression were detected in specimens from 89 cases of patients. We analyzed the correlation between their expressions and histological grade, clinical stage and lymph node metastasis. Notch1, Smad3, Jagged1 and Slug mRNA expressions in TSCC were higher than normal tissue (P <0.05). The protein expression of Notch1 and Smad3 in TSCC were higher (χ(2) =7.30, P <0.01 and χ(2) = 5.84, P <0.05). Notch1 and Smad3 expressions were correlated with clinical stage (χ(2) =18.81, P<0.01; χ(2) =22.29, P<0.01), but not Jagged1 (χ(2) =0.53, P>0.05). The Slug protein expression was correlated with clinical stage. The positive rate of Notch1 was higher in lymph node metastases positive cases (χ(2) =7.30, P<0.01). Moreover, higher expression of Jagged1 was found in lymph node positive cases (χ(2) =10.82, P<0.01). The key protein expression in TGFβ1-Smad3-Jagged1-Notch1-Slug signaling pathway significantly correlated with the clinicopathological features of TSCC patients. It's potential as a biomarker and a novel therapeutic target for TSCC patients at risk of metastasis. It may play an irreplaceable role in TSCC progression which may attribute to promoting EMT which enhances cell migration, invasion and metastasis.

Zhang T ，Liang L ，Liu X ，Wu JN ，Chen J ，Su K ，Zheng Q ，Huang H ，Liao GQ ... -  《-》

Activation of Notch signaling in human tongue carcinoma.

Involvement of Notch signaling in several tumors is well known, but its role in tongue squamous cell carcinoma remains poorly characterized. The purpose of this study was to evaluate the roles of Notch signaling in the oncogenesis of tongue carcinoma. Tumor specimens and adjacent non-neoplastic tongue tissues from 74 patients with tongue carcinoma and human tongue carcinoma cell line Tca8113 were examined using immunohistochemistry and RT-PCR to determine the expressions of Notch1, Notch3, Jagged1, and Jagged2. The mRNA expressions of Notch1, Notch3, Jagged1, and Jagged2 were detected in Tca8113, tongue carcinoma, and adjacent non-neoplastic tongue tissues. The expression levels of mRNAs in tongue carcinoma were higher than those in adjacent non-neoplastic tongue tissues (P < 0.05). Immunohistochemical examination showed that the Notch signal molecules were expressed in Tca8113, tongue carcinoma, and adjacent non-neoplastic tongue tissues. The expression rates of Notch1 and Notch3 protein in tongue carcinoma were higher than those in adjacent non-neoplastic tongue tissues (χ² = 6.10, P = 0.013; χ² = 3.94, P = 0.047). Notch1 and jagged1 were significantly more highly expressed in lymph node metastasis-positive tongue carcinoma (χ² = 6.108, P = 0.013; χ² = 7.354, P = 0.025). In addition, expressions of Notch3 and Jagged2 were highly correlated in tongue carcinoma tissues (χ² = 42.130, P < 0.001). Expressions of Notch receptors and ligands in tongue carcinoma and adjacent non-neoplastic tongue tissues suggest that Notch signaling may control cell differentiation and proliferation of carcinoma cells. The disorder of Notch signaling may be a mechanism of the tongue carcinoma development.

Zhang TH ，Liu HC ，Zhu LJ ，Chu M ，Liang YJ ，Liang LZ ，Liao GQ ... -  《-》

Targeting the ZMIZ1-Notch1 signaling axis for the treatment of tongue squamous cell carcinoma.

Zinc finger MIZ-type containing 1 (ZMIZ1) is a transcriptional coactivator related to the protein inhibitors of activated STATs (PIAS) family. Mounting evidence suggests that ZMIZ1 plays a crucial role in the occurrence and development of cancers. The function of ZMIZ1 in tongue squamous cell carcinoma (TSCC) and the mechanisms underpinning its role in this disease have not been fully clarified. We performed qualitative ZMIZ1 protein expression analyses using immunohistochemistry in 20 patient-derived, paraffin-embedded TSCC tissue sections. We used RNAi to knock down ZMIZ1 expression in the CAL-27 TSCC cell line and quantified the impact of ZMIZ1 knock down on proliferation, migration and apoptosis via CCK-8, scratch assay and flow cytometry, respectively. We used qRT-PCR and western blotting to investigate the role of ZMIZ1 in this cell line. Finally, we established a model of lung metastasis in nude mice to replicate the in vitro results. ZMIZ1 protein was significantly more abundant in TSCC case tissue samples. ZMIZ1 knockdown reduced the invasion and metastases of TSCC tumor cells and promoted apoptosis. ZMIZ1 knockdown was associated with the down-regulation of Notch signaling pathway related factors Jagged1 and Notch1, and invasion and metastasis related factors MKP-1, SSBP2 and MMP7 in vitro and in vivo, at the mRNA level. In vitro and in vivo data suggest that knock down of ZMIZ1 may inhibit TSCC invasion and metastasis by modulating Notch signaling. ZMIZ1 inhibition may therefore represent a new therapeutic target for TSCC.

Pang Y ，Sun Y ，Wu Y ，Li J ，Qin P ，Guo S ，Zhou W ，Chen J ，Wang J ... -  《Scientific Reports》

Notch1 signaling regulates the epithelial-mesenchymal transition and invasion of breast cancer in a Slug-dependent manner.

Shao S ，Zhao X ，Zhang X ，Luo M ，Zuo X ，Huang S ，Wang Y ，Gu S ，Zhao X ... -  《Molecular Cancer》

FoxM1 promotes epithelial-mesenchymal transition, invasion, and migration of tongue squamous cell carcinoma cells through a c-Met/AKT-dependent positive feedback loop.

Yang H ，Wen L ，Wen M ，Liu T ，Zhao L ，Wu B ，Yun Y ，Liu W ，Wang H ，Wang Y ，Wen N ... -  《-》