TY - JOUR
T1 - Induction of tumor initiation is dependent on CD44s in c-Met+ hepatocellular carcinoma
AU - Dang, Hien
AU - Steinway, Steven N.
AU - Ding, Wei
AU - Rountree, Carl B.
N1 - Funding Information:
We acknowledge Drs. Kent Vrana and Willard Freeman of the Functional Genomics Core (The Pennsylvania State University College of Medicine) for technical and editorial input of the manuscript. Important Functional Genomics Core Facility instrumentation purchases were made possible through Tobacco Settlement Funds. This work was made possible by generous support from the National Institute of Health, R03DK088013 (CBR); the American Cancer Society, Research Scholar Award, RSG-10-073-01-TBG (CBR); and the Four Diamonds Foundation (CBR); National Institute of Health, 1F30DK093234-01 (SS).
Funding Information:
Dr. Rountree declares a small research grant (less than $10,000), which does not include direct salary support, from Bayer Pharmaceuticals. Authors WD, SS, and HD declare no potential conflict of interest.
Publisher Copyright:
© Dang et al.
PY - 2015/3/21
Y1 - 2015/3/21
N2 - Background: Hepatocellular carcinoma (HCC) patients with active hepatocyte growth factor (HGF)/c-Met signaling have a significantly worse prognosis. c-Met, a high affinity receptor for HGF, plays a critical role in cancer growth, invasion and metastasis. c-Met and CD44 have been utilized as cell surface markers to identify mesenchymal tumor-initiating stem-like cells (TISC) in several cancers including HCC. In this work, we examine the complex relationship between c-Met and CD44s (standard form), and investigate the specific role of CD44s as a tumor initiator and stemness marker in HCC. Methods: Gene and protein expression assays were utilized to investigate the relationship between CD44s and c-Met in HCC cell lines. Tumor-sphere assays and in vivo tumor assays were performed to investigate the role of CD44+ cells as TISCs. Student's t-test or one-way ANOVA with Tukeys post-hoc test was performed to test for differences amongst groups with a p<.05 as significant. Results: In an immunohistochemical and immunoblot analysis of human HCC samples, we observed that more than 39% of human HCC samples express c-Met and CD44. To study the relationship between c-Met and CD44, we used MHCC97-H cells, which are CD44+/c-Met+. The knockdown of c-Met in MHCC97-H cells decreased CD44s, reduced TISC characteristics and decreased tumorsphere formation. Furthermore, we demonstrate that the inhibition of PI3K/AKT signaling decreased CD44s expression and subsequently decreased tumorsphere formation. The down-regulation of CD44s leads to a significant loss of a TISC and mesenchymal phenotype. Finally, the down-regulation of CD44s in MHCC97-H cells decreased tumor initiation in vivo compared with the scrambled control. Conclusions: In summary, our data suggest that CD44s is modulated by the c-Met-PI3K-AKT signaling cascade to support a mesenchymal and TISC phenotype in HCC cells. Moreover, c-Met could be a potential therapeutic drug for targeting HCC cells with TISC and mesenchymal phenotypes.
AB - Background: Hepatocellular carcinoma (HCC) patients with active hepatocyte growth factor (HGF)/c-Met signaling have a significantly worse prognosis. c-Met, a high affinity receptor for HGF, plays a critical role in cancer growth, invasion and metastasis. c-Met and CD44 have been utilized as cell surface markers to identify mesenchymal tumor-initiating stem-like cells (TISC) in several cancers including HCC. In this work, we examine the complex relationship between c-Met and CD44s (standard form), and investigate the specific role of CD44s as a tumor initiator and stemness marker in HCC. Methods: Gene and protein expression assays were utilized to investigate the relationship between CD44s and c-Met in HCC cell lines. Tumor-sphere assays and in vivo tumor assays were performed to investigate the role of CD44+ cells as TISCs. Student's t-test or one-way ANOVA with Tukeys post-hoc test was performed to test for differences amongst groups with a p<.05 as significant. Results: In an immunohistochemical and immunoblot analysis of human HCC samples, we observed that more than 39% of human HCC samples express c-Met and CD44. To study the relationship between c-Met and CD44, we used MHCC97-H cells, which are CD44+/c-Met+. The knockdown of c-Met in MHCC97-H cells decreased CD44s, reduced TISC characteristics and decreased tumorsphere formation. Furthermore, we demonstrate that the inhibition of PI3K/AKT signaling decreased CD44s expression and subsequently decreased tumorsphere formation. The down-regulation of CD44s leads to a significant loss of a TISC and mesenchymal phenotype. Finally, the down-regulation of CD44s in MHCC97-H cells decreased tumor initiation in vivo compared with the scrambled control. Conclusions: In summary, our data suggest that CD44s is modulated by the c-Met-PI3K-AKT signaling cascade to support a mesenchymal and TISC phenotype in HCC cells. Moreover, c-Met could be a potential therapeutic drug for targeting HCC cells with TISC and mesenchymal phenotypes.
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U2 - 10.1186/s12885-015-1166-4
DO - 10.1186/s12885-015-1166-4
M3 - Article
C2 - 25886575
AN - SCOPUS:84925872508
VL - 15
JO - BMC Cancer
JF - BMC Cancer
SN - 1471-2407
IS - 1
M1 - 161
ER -