The Study On The Signal Network Of Shp2in HCC Progression And The Clinical Significance

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the worldand the second leading cause of cancer death in men[1]. Despite the current advance inthe hepatic resection and transplantation, long-term survival of HCC patients remainsunsatisfactory due to the high incidence of recurrence and metastasis after surgicalresection[2]. It has been reported that HCC recurrence rate exceeds70%at5years[3].Therefore, it is urgent to identify novel therapeutic targets so that new strategies forHCC treatment can be developed. Accumulating genetic and functional studies ofoncogenes and tumor suppressor genes have greatly contributed to the advance ofknowledge on the molecular mechanism of tumorigenesis[4]. Inside the cancer cells,various signaling pathways are regulated by some predominant hub molecules at thebiochemical levels[5,6]. Tyrosine phosphorylation and dephosphorylation of these keymolecules plays critical roles in the regulatory network and aberrant tyrosinephosphorylation has been frequently detected in various cancers[5,7].Shp2, encoded by PTPN11, was first identified by us and other groups in the early1990s as a non-receptor protein tyrosine phosphatases containing two Src-homology2(SH2) domains[8-10]. In the following two decades, accumulating studies documentedthat Shp2acts as a transducer of extracellular pro-survival and proliferation signalsfrom various cytokines, growth factors and hormones[11,12]. Shp2is required for theamplification of ERK signaling upon distinct mitogenic stimuli[11]. In previous work,we generated a hepatocyte-specific Shp2knockout (Shp2hepâ–³) mouse model, andreported that Shp2deletion attenuated Erk activation and hepatocyte proliferationfollowing partial hepatectomy[13]. Nevertheless, effect of Shp2on the modulation ofPI3-K/Akt pathways and Jak/STAT cascade is cell specific or stimuli specific[14-16]. Inaddition, mouse genetics and sequencing studies have also indicated a broad role forShp2in development and disease[17,18].Genetically, Ptpn11mutation has been detected in up to50%of patients withNoonan syndrome, a kind of developmental disorder, and the patients possess strkingly higher risk of juvenile myelomonocytic leukemia (JMML)[19]. Constitutiveactivation of Shp2by somatic mutations are present in different types of leukemia, andShp2has been considered as a proto-oncogene in leukemia[20,21]. Shp2has beendocumented to hyperactivated by oncogenes in gastric carcinoma, anaplastic large-celllymphoma and glioblastoma[22-24]. However, Ptpn11mutation has been scarcelydetected in solid tumors including hepatoma[25,26]. Our most current data indicated thetumor-inhibiting effect of Ptpn11/Shp2in carcinogenesis via downregulation ofinflammatory signaling. We found that Shp2deficience in hepatocytes causes chronichepatic damage and injury, which triggers inflammation and compensatory hepatocyteproliferation and thus promotes tumorigenesis in the liver, after a long latent period oftime[27]. Nevertheless, it is interesting that overexpression of Shp2was detected in thevast majority of HCC samples. Herein, we found Shp2acts as hub molecule regulatingseveral key cancer-related signaling in hepatoma cells and could serve as a promisingprognosis biomarker and therapeutic target for HCC therapy.So our purpose of this project is to design a series of related experiments toobserve the role of Shp2on HCC recurrence and metastasis,clarify the molecularbiological mechanism and the clinical significance of Shp2on HCC development, andprovided a theoretical and experimental basis for targeted therapy of HCC.