Sivi teğetsel gerilme stresinin hepatoselüler karsinoma hücrelerinin biyolojik davranişlarina C-met sinyal yolaği aracilikli etkilerinin araştirilmasi

Tumour metastasis is the most common reason of the cancer related death. Metastasis process requires cancer cells to detach primer tumour and intravasation to blood circulation and survive the shear stress in blood stream, homing and proliferation in the secondary organ. Fluidic shear stress (FSS) in blood circulation effects tumour cell's survival, apoptosis, invasion, metastasis and proliferation. Several clinic-pathological studies underline that in HCC intravascular invasion is poor prognosis factor and it is significantly important in metastasis. When tumour cells intravasate to sinusoidal capillaries, shear stress stimulate apoptosis. Frequency of intrahepatic metastasis is high in HCC and it occurs as invasion dependent manner indicating survival of tumour cells under FSS is crucial step for intrahepatic and extrahepatic metastasis. Nevertheless mechanisms behind process hasn't been illuminated adequately yet. Our previous studies showed that HGF/c-Met pathway plays crucial role in cell survival, invasion, metastasis during hepatocarcinogenesis. In this study we aimed to examine the role of HGF/c-Met pathway on survival and proliferation of HCC cells under FSS. In order to do this, we used peristaltic pump to apply FSS to HCC cells which have low (HuH-7 and HepG2) and high (SNU-449) c-Met levels. c-Met expression and activation levels were determined by RT-qPCR and Western blotting, cell survival and proliferation analysis by trypan blue and (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)(MTT) in HCC cells. The effect of FSS on colony formation, epithelial-mesenchymal transition (EMT) and invasion were determined by 3D microfluidic system. Our data showed that, FSS treatment increased the expression and activation of c-Met stimulating EMT phenotype, cell survival, proliferation and invasion in HCC cells and c-Met inhibitor (SU11274) reversed these effects suggesting HGF/c-Met pathway has critical role on the survival of HCC cells under FSS and induces aggressive phenotype and c-Met inhibitors could be used to inhibit survival of circulating tumour cells' metastasis in HCC.