Title: ST6GALNAC1 plays important roles in enhancing cancer stem phenotypes of colorectal cancer via the Akt pathway
Abstract: // Tadashi Ogawa 1, 2 , Yoshihiko Hirohashi 1 , Aiko Murai 1 , Toshihiko Nishidate 2 , Kenji Okita 2 , Liming Wang 1 , Yuzuru Ikehara 3 , Tetsuta Satoyoshi 1, 2 , Akihiro Usui 1, 2 , Terufumi Kubo 1 , Munehide Nakastugawa 1 , Takayuki Kanaseki 1 , Tomohide Tsukahara 1 , Goro Kutomi 2 , Tomohisa Furuhata 2 , Koichi Hirata 2 , Noriyuki Sato 1 , Toru Mizuguchi 2 , Ichiro Takemasa 2 and Toshihiko Torigoe 1 1 Department of Pathology, Sapporo Medical University School of Medicine, Chuo-Ku, Sapporo 060-8556, Japan 2 Department of Surgery, Sapporo Medical University School of Medicine, Chuo-Ku, Sapporo 060-8556, Japan 3 The Molecular Medicine Team, Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology, Tsukuba 305-8568, Japan Correspondence to: Yoshihiko Hirohashi, email: [email protected] Toshihiko Torigoe, email: [email protected] Keywords: colorectal cancer, cancer stem cell, ST6GALNAC1, STn antigen, Akt pathway Received: June 16, 2017 Accepted: October 04, 2017 Published: November 08, 2017 ABSTRACT Colorectal cancer (CRC) is a mortal disease due to treatment resistance, recurrence and distant metastasis. Emerging evidence has revealed that a small sub-population of cancer cells termed cancer stem cells (CSCs)/ cancer-initiating cells (CICs) is endowed with high levels of tumor-initiating ability, self-renewal ability and differentiation ability and is responsible for treatment resistance, recurrence and distant metastasis. Eradication of CSCs/CICs is essential to improve current treatments. However, the molecular mechanisms by which CSCs/CICs are maintained are still elusive. In this study, we aimed to determine the molecular mechanisms by which colorectal (CR)-CSCs/CICs in are maintained human primary CRC cells. CR-CSCs/CICs were isolated by sphere-culture and the ALDEFLUOR assay, and transcriptome analysis revealed that the gene ST6 N-Acetylgalactosaminide Alpha-2,6-Sialyltransferase 1 (ST6GALNAC1) was expressed at high levels in CR-CSCs/CICs. Overexpression of ST6GALNAC1 enhanced the expression of sialyl-Tn (STn) antigen, which is carried by the CSC marker CD44, and increased the sphere-forming ability and resistance to a chemotherapeutic reagent. The opposite phenomena were observed by gene knockdown using siRNA. Furthermore, the Akt pathway was activated in ST6GANAC1-overexpressed cells, and activation of the pathway was cancelled by gene knockdown of galectin-3. The results indicate that ST6GALNAC1 has a role in the maintenance of CR-CSCs/CICs by activating the Akt pathway in cooperation with galectin-3 and that ST6GalNAC1 (or STn antigen) might be a reasonable molecule for CSC/CIC-targeting therapy.