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Jingjing Jiao,Álvaro González,Heather L Stevenson,Mihai Gagea,Hikaru Sugimoto,Raghu Kalluri,Laura Beretta 생화학분자생물학회 2018 Experimental and molecular medicine Vol.50 No.-
There is a pressing need for the development of novel approaches to treat and prevent hepatocellular carcinoma (HCC). The S100 calcium-binding protein S100A4 is associated with poor prognosis and metastasis in several human cancers. In addition, a role for S100A4 in modulating cancer-initiating cells stemness properties was recently proposed in head and neck and gastric cancers. Whether S100A4+ stromal cells contribute to tumor onset remains, however, an unanswered question. To address that question, we generated a new mouse model allowing for the depletion of S100A4+ cells in a mouse model of HCC with stemness properties, by crossing mice with hepatic deletion of phosphatase and tensin homolog (PTEN) with mice expressing viral thymidine kinase under the control of S100A4 promoter. Depletion of S100A4+ cells by ganciclovir injection did not prevent the development of HCC but reduced the stemness phenotype of the tumor as measured by the expression of progenitor cell, biliary cell and hepatocyte markers. The results were further confirmed by histology analysis showing reduction of cholangiolar tumor components and degree of oval cell hyperplasia in the adjacent liver. Depletion of S100A4+ cells had also some beneficial effect on the underlying liver disease with a reduction of NAS score, largely due to the reduction of inflammation. In conclusion, this study demonstrated that S100A4+ cells do not contribute to HCC onset but maintain the stemness phenotype of the tumor. This study also suggests for the first time a crosstalk between inflammation and stemness.
Development and characterization of six new human papillary thyroid carcinoma cell lines.
Henderson, Ying C,Ahn, Soon-Hyun,Ryu, Junsun,Chen, Yunyun,Williams, Michelle D,El-Naggar, Adel K,Gagea, Mihai,Schweppe, Rebecca E,Haugen, Bryan R,Lai, Stephen Y,Clayman, Gary L Issued for the Endocrine Society by the Williams & 2015 The Journal of clinical endocrinology & metabolism Vol.100 No.2
<P>Cell lines are a widely used tool in cancer research. However, despite the relatively high incidence of papillary thyroid carcinoma (PTC), there are only four PTC cell lines available for international research audience.</P>
Wang, Chao,Gu, Chao,Jeong, Kang Jin,Zhang, Dong,Guo, Wei,Lu, Yiling,Ju, Zhenlin,Panupinthu, Nattapon,Yang, Ji Yeon,Gagea, Mihai (Mike),Ng, Patrick Kwok Shing,Zhang, Fan,Mills, Gordon B. American Association for Cancer Research 2017 Cancer Research Vol.77 No.7
<P>Interactions between HIPPO, YAP/TAZ, and the PI3K/AKT pathway may be therapeutically targetable, providing new approaches to treating endometrial cancers and other cancers where the HIPPO pathway is a core oncogenic driver.</P><P>The transcription regulators YAP and TAZ function as effectors of the HIPPO signaling cascade, critical for organismal development, cell growth, and cellular reprogramming, and YAP/TAZ is commonly misregulated in human cancers. The precise mechanism by which aberrant YAP/TAZ promotes tumor growth remains unclear. The HIPPO tumor suppressor pathway phosphorylates YAP and TAZ, resulting in cytosolic sequestration with subsequent degradation. Here, we report that the PI3K/AKT pathway, which is critically involved in the pathophysiology of endometrial cancer, interacts with the HIPPO pathway at multiple levels. Strikingly, coordinate knockdown of YAP and TAZ, mimicking activation of the HIPPO pathway, markedly decreased both constitutive and growth factor–induced PI3K pathway activation by decreasing levels of the GAB2 linker molecule in endometrial cancer lines. Furthermore, targeting YAP/TAZ decreased endometrial cancer tumor growth <I>in vivo</I>. In addition, YAP and TAZ total and phosphoprotein levels correlated with clinical characteristics and outcomes in endometrial cancer. Thus, YAP and TAZ, which are inhibited by the HIPPO tumor suppressor pathway, modify PI3K/AKT pathway signaling in endometrial cancer. The cross-talk between these key pathways identifies potential new biomarkers and therapeutic targets in endometrial cancer. <I>Cancer Res; 77(7); 1637–48. ©2017 AACR</I>.</P>