The Function and Mechanism of Ribonuclease 4 in Prostate Cancer
cancer is the most common cancer in American men, representing 19 percent of all cancers
diagnosed in males. The most prominent biomarker utilized for prostate cancer screening
and diagnosis is prostate specific antigen (PSA). Unfortunately, limitations of PSA
testing, including inability to distinguish cancer from benign disease, inefficiency in
predicting cancer aggressiv... read moreeness and low specificity, have led to overtreatment of
prostate cancer in the clinic and propelled the scientific community to explore superior
prostate cancer biomarkers that can discriminate indolent from aggressive disease and
aid in clinical decision-making regarding need for biopsy and type of treatment. In this
thesis, we report that secreted ribonuclease 4 (RNASE4) protein may serve as such a
biomarker as well as therapeutic target. RNASE4 expression is significantly elevated in
prostate cancer patients and positively correlates with advanced disease stage, grade,
Gleason score, and risk. Therefore, plasma RNASE4 level may stratify patients for biopsy
and/or treatment type as it provides valuable information on cancer aggressiveness and
independently predicts biopsy outcome. Functionally, RNASE4 induces cancer cell
proliferation and tumor angiogenesis. Mechanistically, RNASE4 activates AXL, a tyrosine
kinase receptor known to drive cancer metastasis and therapeutic resistance, and
downstream signal transduction pathway, PI3K-AKT-mTOR, to stimulate cancer cell
proliferation. This is the first study to demonstrate the function and mechanism of
RNASE4 in cancer. Work described in this thesis also demonstrates RNASE4 undergoes
receptor-mediated endocytosis and AXL may serve as a cell surface receptor for RNASE4.
Studies presented here show that RNASE4 physically interacts with AXL to induce its
autophosphorylation, acting as a putative ligand for AXL. Therapeutically, inhibition of
RNASE4 activity by monoclonal antibody decelerate tumor angiogenesis, cancer cell
proliferation and growth of xenograft tumors in both prophylactic and therapeutic
settings. Importantly, RNASE4 inhibition resulted in a reduction of AXL phosphorylation
in prostate cancer xenograft animal models. Together, these findings demonstrate the
functional importance of RNASE4 in prostate cancer, and suggest that RNASE4 may
simultaneously serve as a prognosis marker and therapeutic target for high risk prostate
Thesis (Ph.D.)--Tufts University, 2017.
Submitted to the Dept. of Biochemistry.
Advisor: Guofu Hu.
Committee: Alexei Degterev, Philip Tsichlis, and Larry Feig.
Keywords: Biochemistry, Biology, and Pharmacology.read less