RalA signaling pathway as a therapeutic target in hepatocellular carcinoma (HCC).
Ral (Ras like) leads an important proto-oncogenic signaling pathway down-stream of Ras. In this work, RalA was found to be significantly overactivated in hepatocellular carcinoma (HCC) cells and tissues as compared to non-malignant samples. Other elements of RalA pathway such as RalBP1 and RalGDS were also expressed at higher levels in malignant samples. Inhibition of RalA by gene-specific silencing caused a robust decrease in the viability and invasiveness of HCC cells. Additionally, the use of geranyl-geranyl transferase inhibitor (GGTI, an inhibitor of Ral activation) and Aurora kinase inhibitor II resulted in a significant decrease in the proliferation of HCC cells. Furthermore, RalA activation was found to be at a higher level of activation in HCC stem cells that express CD133. Transgenic mouse model for HCC (FXR-Knockout) also revealed an elevated level of RalA-GTP in the liver tumors as compared to background animals. Finally, subcutaneous mouse model for HCC confirmed effectiveness of inhibition of aurora kinase/RalA pathway in reducing the tumorigenesis of HCC cells in vivo. In conclusion, RalA overactivation is an important determinant of malignant phenotype in differentiated and stem cells of HCC and can be considered as a target for therapeutic intervention.
The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA.
Mohamad
M
Ezzeldin
The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA.
Emma
E
Borrego-Diaz
The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA.
Mohammad
M
Taha
The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA.
Tuba
T
Esfandyari
The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA.
Amanda L
AL
Wise
The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA.
Warner
W
Peng
The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA.
Alex
A
Rouyanian
The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA.
Atabak
A
Asvadi Kermani
The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA.
Mina
M
Soleimani
The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA.
Elham
E
Patrad
The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA.
Kristina
K
Lialyte
The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA.
Kun
K
Wang
The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA.
Stephen
S
Williamson
The University of Kansas Medical Center, Department of Surgery, Kansas City, KS, USA.
Bashar
B
Abdulkarim
The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA.
Mojtaba
M
Olyaee
The University of Kansas Medical School, Divisions of Gastroenterology, Hepatology and Motility and Hematology/Oncology, Molecular Medicine Laboratory, Kansas City, KS, USA. Electronic address: ffarassati@kumc.edu.
Faris
F
Farassati
D000818:Animals; D064127:Aurora Kinases / Q000037:antagonists & inhibitors; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D020725:ral GTP-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*
D047428:Protein Kinase Inhibitors; D064127:Aurora Kinases; C492198:RALA protein, human; D020725:ral GTP-Binding Proteins
Aurora kinase; Cancer stem cells; FXR; HCC; Ral; RalBP1; Signaling; Treatment