Overexpression of Hepatoma-Derived Growth Factor (HDGF) is Associated with Invadopodia Formation and Worse Prognosis in Upper Tract Urothelial Carcinoma

Bi-Wen Yeh 1,2,7, Wei-Ming Li1,2,3*, Ming-Hong Tai4,7, Ching-Chia Li1,2,5, Chien-Feng Li6, Hung-Lung Ke1,2, Hsin-Chi Yeh1,2,5, Hiang-Ying Lee1,2,5, Wen-Jeng Wu1,2,5,7*

葉碧雯 ，李威明，戴明泓，李經家，李健逢，柯宏龍，葉信志，李香瑩，吳文正

1Department of Urology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, 2Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, 3Department of Urology, Ministry of Health and Welfare Pingtung Hospital, Pingtung, Taiwan, 4Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan, 5Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan, 6Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan, 7Center of Stem cell Research, Kaohsiung Medical University

Purpose: Hepatoma-derived growth factor (HDGF) is a nucleus targeted growth factor, it has been reported to exert mitogenic effects on several types of cells and elevated in various types of cancers suggesting an important role in the development and progression of cancers. Our study was designed to elucidate the correlation of HDGF expression and prognosis in patients with upper urinary tract urothelial carcinoma (UTUC). Invadopodia (actin-rich protrusions structures associated with extracellular matrix (ECM) degradation formed by aggressive cancer cells) have an essential role in invasion. Although the role of HDGF in invadopodia has been assumed to signaling and actin assembly, it is incompletely understood. The related molecular mechanisms of HDGF involved in UC invasion and invadopodia formation were investigated. Patients and Methods: One hundred and fifty-eight UTUC specimens were analyzed for HDGF by immunohistochemistry. HDGF expression in urothelial cancer cell lines was analyzed by RT-PCR and western blotting. In vitro characterizations of the cellular function of recombinant HDGF in epithelial-mesenchymal transition (EMT) and tumorigenic behaviors by trans-well assay and colony formation assay, respectively. The role of HDGF signaling on regulates invadopodia formation and ECM degradation was assessed by gelatin matrix degradation assay. Results and Conclusions: Overexpression of HDGF was present in 74 patients (46.8%). A positive HDGF expression was significantly associated with higher disease progression (p = 0.036) and cancer-related death rates (p = 0.001). In vitro study showed that overexpression of HDGF in UC cells could significantly increase their cellular proliferation, colonies formation, migration, invasion and invadopodia formation through the PI3K/AKT pathway. Knockdown of HDGF high expression UC cells with its specific shRNA inhibited the growth ability using colonies formation experiments. Our study demonstrates that HDGF overexpression is associated with aggressive biological behavior of UC cells, act via the PI3K/AKT pathway. HDGF expression status may represent a prognostic prediction biomarker for patients with invasive UTUC after nephroureterectomy. Further investigating the potential therapeutic role of HDGF in the treatment of UC patients is undertaken.