title: CD133 confers cancer stem-like cell properties by stabilizing EGFR-AKT signaling in hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) is the seventh most common malignant tumor and the third leading cause of cancer-related death in the world. Cancer stem cells (CSCs) are small subpopulation of cells within tumors that drive chemoresistance and tumor recurrence in various cancers. We characterized CSCs in primary HCC and identified CD133 as a CSC surface marker. CD133+HCC cells displayed more stem cell-like properties, tumor spheroid-forming ability, chemoresistance, migration ability, and tumorigenic capacity than CD133-HCC cells. The biological function and molecular mechanism of CD133 remain unclear. HCC cell lines with a high level of CD133 expression overexpressed EGFR, which is overexpressed in approximately 70% of conventional HCCs. CD133 depletion destabilized EGFR by augmenting EGFR internalization and thus inhibited EGFR-AKT signaling. CD133 would therefore serve to sustain aberrant EGFR-mediated oncogenic signaling. Furthermore, EGFR-deficient CD133+HCC cells manifested greater sensitivity to anticancer drugs and less spheroid-formation capacity than control CD133+HCC cells. Our results strongly indicate that CD133 facilitates CSC-like properties by stabilizing EGFR-AKT signaling in HCC. It might therefore be feasible to use CD133 as a novel target to sensitize HCC cells that manifest resistance to EGFR-targeted therapy.
authors.affiliation: Laboratory of Biochemistry, Division of Life Sciences, Korea University, 145, Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea.
authors.forename: Jae-Woo
authors.initials: JW
authors.lastname: Jang
authors.affiliation: Cancer Biology Research Laboratory, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea; Laboratory of Biochemistry, Division of Life Sciences, Korea University, 145, Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea.
authors.forename: Yeonhwa
authors.initials: Y
authors.lastname: Song
authors.affiliation: Cancer Biology Research Laboratory, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea.
authors.forename: Se-Hyuk
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Division of Gastroenterology and Hepatology, ASAN Medical Center, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.
authors.forename: Jin-Sun
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Division of Gastroenterology and Hepatology, ASAN Medical Center, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.
authors.forename: Kang Mo
authors.initials: KM
authors.lastname: Kim
authors.affiliation: Division of Radiation Oncology, ASAN Medical Center, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Choi
authors.affiliation: Laboratory of Biochemistry, Division of Life Sciences, Korea University, 145, Anam-ro, Seongbuk-gu, Seoul, 02841, Republic of Korea. Electronic address: joonkim@korea.ac.kr.
authors.forename: Joon
authors.initials: J
authors.lastname: Kim
authors.affiliation: Cancer Biology Research Laboratory, Institut Pasteur Korea, 16, Daewangpangyo-ro 712 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea. Electronic address: shr1261@ip-korea.org.
authors.forename: Haeng Ran
authors.initials: HR
authors.lastname: Seo
mesh_terms: D000071916:AC133 Antigen / Q000032:analysis / Q000502:physiology*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000737:chemistry / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000502:physiology*; D006801:Humans; D008113:Liver Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D018874:Spheroids, Cellular
chemical_list: D000071916:AC133 Antigen; C000606023:PROM1 protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt
keywords: CD133; Cancer stem cells (CSCs); Epidermal growth factor receptor (EGFR); Hepatocellular carcinoma (HCC)