Fas-associated Protein With Death Domain(FADD) Regulation Of Cell Migration By Promoting The Expression Of Focal Adhesion Kinase(FAK) And Study Of Its Non-apoptotic Function

Fas-associated protein with death domain(FADD),a classical adaptor protein mediating apoptotic stimuli-induced cell death by its C-terminal death domain’s binding with the death domain of the receptor of Fas/CD95,has been reported to engage in several non-apoptotic processes such as cell proliferation,embryonic development,angiogenesis,tumorigenesis and metastasis.However,the field of FADD in tumor metastasis is still new and the mechanisms remain elusive.Focal adhesion kinase(FAK)is known as a non-receptor tyrosine kinase which plays a key role in signal transduction pathways that are initiated at sites of integrin-mediated cell adhesions and by growth factor receptors.It is an important regulator of several processes involved in the development and progression of cancer,such as cell survival,proliferation,migration and invasion.FAK is also linked to different oncogenes and overexpressed in a wide variety of cancers,inmplicating its role in cancinogenesis,acting as a biomarker.Here we presented an unexpected finding that FADD could regulate the expression of FAK in murine MEF and B16F10 cells.Moreover,miR-7a,a normal tumor suppressor which prohibits cell migration and invasion,was up-regulated in FADD-defecient cells.To explore the mechanism between these three objects,we verified FAK was a direct target gene of miR-7a and could be inhibited by miR-7a.Furthermore,in contrast to its classical apoptotic roles,we found FADD interference could reduce the rate of cell migration,which could be rescued by inhibiting miR-7a expression in murine melanoma cells.Taken together,the data of this thesis provides new explanation regarding how FADD regulates cell migration in murine melanoma.FADD usually acts as a tumor suppressor in many kinds of cancers,expressing a low level in those tumors such as thymic lymphoma,thyroid tumors,etc.However,it shows a really high expression level in some other cancers like lung,breast,head and neck squamous cell carcinoma.This paper also provides a data of high expression level of FADD in several human pancreatic cancer cells.Since pancreatic cancer is one of the leading lethal cancers that are highly resistant to chemotherapy.Identifying molecular mechanisms involved in drug resistance is critical to develop novel strategies to treat pancreatic cancer.Here we present an interesting finding that FADD,the classical adaptor protein mediating apoptotic stimuli-induced cell death,protects pancreatic cancer cells from drug-induced apoptosis.In contrast to its classical apoptotic roles,we found that FADD is required for pancreatic cancer cells proliferation and is overexpressed with varying degrees in different pancreatic cancer cells,which cause different degrees of drug resistance.That is,the pancreatic cancer cell with higher FADD expression level has higher drug resistance.More importantly,our data show that FADD protects pancreatic cancer cells from drug-induced apoptosis and RNA interference of FADD sensitizes drug-resistant cells to Adriamycin-mediated apoptosis.Taken together,our data also reveal unexpected roles of FADD in proliferation and drug resistance in pancreatic cancer cells.