• Identification of microRNA associated with chemoresistance and stemness in pancreatic cancer (Br. J Cancer, 111, 1572, 2014)

    Pancreatic cancer has a poor prognosis because of its high refractoriness to chemotherapy and tumor recurrence, and these properties have been attributed to cancer stem cells (CSCs). MicroRNA (miRNA) regulates various molecular mechanisms of cancer progression associated with CSCs. This study aimed to identify the candidate miRNA and to characterize the clinical significance. In collaboration with Osaka University and Tokyo University, Hasegawa et al. established chemo-resistant pancreatic cancer cells, and induced CSC-like properties through sphere formation. Candidate miRNAs were selected through microarray analysis. The overexpression and knockdown experiments were performed by evaluating the in vitro cell growth and in vivo tumorigenicity. The expression was studied in pancreatic cancer samples after laser captured microdissection and by immunohistochemical staining. The in vitro drug sensitivity of pancreatic cancer cells was altered according to the miR expression via a target. In vivo, we found that the miR could increase tumor-initiating potential and induced drug resistance. A high expression level of miR was correlated with a worse prognosis and the target expression was significantly lower in those patients.The data indicated that the miR expression was associated with chemoresistance and CSC-like properties via a target pathway, and could predict worse prognosis in pancreatic cancer patients. Detailed information will be available in publication.

  • Oxidative phosphorylation in colorectal cancer: roles of hexokinase 2 and phosphorylated pyruvate dehydrogenase-E1α in invasive front lesions (Cancer Science , 105, 1100-1108, 2014)

    Although numerous studies have shown the significance of cancer-specific aerobic glycolysis, how glycolysis contributes to tumor invasion, a critical phenomenon in metastasis, remains unclear. In collaboration with the Department of Surgery, Osaka University, Hamabe et al. studied two critical gate enzymes, hexokinase 2 (HK2), which is involved in glycolysis, and phosphorylated pyruvate dehydrogenase-E1α (p-PDH), which is involved in oxidative phosphorylation (OxPhos) in colorectal cancer (CRC). The combined evaluation of positive HK2 and negative p-PDH was associated with reduced recurrence-free survival (RFS). This evaluation could predict RFS more precisely than the independent evaluation. The present study indicated that high HK2 expression combined with low p-PDH expression in the invasive front lesions of CRC tumors is predictive of tumor aggressiveness and survival of CRC cases.

  • Novel cancer stem cell marker CD10 in HNSCC (Br. J. Cancer, 111, 506-514, 2014)

    In the collaboration with Department of Otorhinolaryngology-Head and Neck Surgery, Osaka University, Fukusumi et al. found CD10 as a novel marker of therapeutic resistance and cancer stem cells in head and neck squamous cell carcinoma. By studying three HNSCC cell lines (FaDu, Detroit562, and BICR6), treated with cisplatin or radiation, cell surface antigens were analysed by LyoPlateTM, a novel cell surface antigen array. The expression levels of antigens highly expressed after treatments were further compared between cisplatin-resistant Detroit562 cells and its parental line. Association of the candidate antigen with CSCs properties, namely sphere formation and in vivo tumourigenicity, was also examined. The result indicated that CD10, CD15s, CD146, and CD282 were up-regulated across the treated cell lines, while the increased expression of CD10 was prominent in the cisplatin-resistant cell line. FACS-mediated isolation revealed that the CD10-positive subpopulation was more refractory to cisplatin, fluorouracil, and radiation than the CD10-negative subpopulation. It also showed an increased ability to form spheres in vitro and tumours in vivo. Moreover, the CD10-positive subpopulation expressed the CSC marker OCT3/4 at a higher level than that in the CD10-negative subpopulation. Thus CD10 is associated with therapeutic resistance and CSC-like properties of HNSCC. CD10 may serve as a target molecule in the treatment of refractory head and neck squamous cell carcinoma (HNSCC).