Navchaa Gombodorj1,2, Yoko Azuma3, Takehiko Yokobori4, Bilguun Erkhem-Ochir5, Takayuki Kosaka5, Yoichi Ohtaki5, Seshiru Nakazawa5, Akira Mogi5, Toshiki Yajima5, Hiroyuki Kuwano5, Hiroshi Saeki5, Ken Shirabe5. 1. Division of Integrated Oncology Research, Gunma University, Initiative for Advanced Research (GIAR), Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan. 2. Department of Radiation Oncology, National Cancer Center, Ulaanbaatar, Mongolia. 3. Division of Chest Surgery, Department of Surgery, Toho University School of Medicine, Tokyo, Japan. 4. Division of Integrated Oncology Research, Gunma University, Initiative for Advanced Research (GIAR), Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan. bori45@gunma-u.ac.jp. 5. Departments of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
Abstract
BACKGROUND: Fibroblast growth factor receptor (FGFR)-signaling in lung squamous cell carcinoma (LSCC) is associated with cancer aggressiveness and poor prognosis. Small GTPase RAB11A regulates the recycling of membrane proteins such as FGFR. This study evaluated the potential of RAB11A as a new therapeutic target for LSCC through its regulation of FGFR-signaling. METHODS: Immunohistochemical analysis of 84 LSCC samples was performed to determine the correlation between RAB11A expression, clinicopathologic features, and prognosis. Alterations in FGFR-signaling were assessed in RAB11A-suppressed and RAB11A-overexpressed LSCC cells both in vitro and in vivo. RESULTS: The study identified RAB11A as a strong predictor of poor prognosis in the LSCC cohort. Cell proliferation and invasion were promoted and inhibited respectively in RAB11A-overexpressed and RAB11A -suppressed LSCC cells. In RAB11A-overexpressed and RAB11A-suppressed LSCC cells, FGFR-signaling was respectively up- and downregulated. The viability of the cells treated with nintedanib and lenvatinib was greater in RAB11A-overexpressing cells than in control cells. The in vivo tumor growth and micro-vessel density of RAB11A-overexpressing tumors were significantly higher than in the control cells. CONCLUSION: As a potentially valuable prognostic marker, RAB11A is a promising therapeutic target for LSCC. Evaluation of RAB11A may be useful for identification of LSCC in patients whose cancer is refractory to FGFR inhibitors.
BACKGROUND: Fibroblast growth factor receptor (FGFR)-signaling in lung squamous cell carcinoma (LSCC) is associated with cancer aggressiveness and poor prognosis. Small GTPase RAB11A regulates the recycling of membrane proteins such as FGFR. This study evaluated the potential of RAB11A as a new therapeutic target for LSCC through its regulation of FGFR-signaling. METHODS: Immunohistochemical analysis of 84 LSCC samples was performed to determine the correlation between RAB11A expression, clinicopathologic features, and prognosis. Alterations in FGFR-signaling were assessed in RAB11A-suppressed and RAB11A-overexpressed LSCC cells both in vitro and in vivo. RESULTS: The study identified RAB11A as a strong predictor of poor prognosis in the LSCC cohort. Cell proliferation and invasion were promoted and inhibited respectively in RAB11A-overexpressed and RAB11A -suppressed LSCC cells. In RAB11A-overexpressed and RAB11A-suppressed LSCC cells, FGFR-signaling was respectively up- and downregulated. The viability of the cells treated with nintedanib and lenvatinib was greater in RAB11A-overexpressing cells than in control cells. The in vivo tumor growth and micro-vessel density of RAB11A-overexpressing tumors were significantly higher than in the control cells. CONCLUSION: As a potentially valuable prognostic marker, RAB11A is a promising therapeutic target for LSCC. Evaluation of RAB11A may be useful for identification of LSCC in patients whose cancer is refractory to FGFR inhibitors.
Authors: Katharina Schmidt; Christian Moser; Claus Hellerbrand; Derek Zieker; Christine Wagner; Julia Redekopf; Hans J Schlitt; Edward K Geissler; Sven A Lang Journal: Anticancer Res Date: 2015-12 Impact factor: 2.480