title: Human telomerase reverse transcriptase (hTERT) promotes cancer invasion by modulating cathepsin D via early growth response (EGR)-1.
abstract: Human telomerase reverse transcriptase (hTERT) contributes to tumor progression as well as maintaining telomere length, however, the mechanism by which hTERT promotes invasiveness is not yet completely understood. This study aims to unravel the precise mechanism through which hTERT promotes cancer invasion. We established an hTERT-overexpressed immortalized cell line (IHOK/hTERT). In orthotopic xenograft models, IHOK/hTERT harbors higher tumorigenicity than IHOK/Control. IHOK/hTERT showed much higher migration and invasion activities compared to IHOK/Control. IHOK/hTERT co-cultured with fibroblasts displayed increased invasion compared to IHOK/hTERT without fibroblasts. We screened for genes that play an important role in intermodulation between cancer cells and fibroblasts using a microarray and identified fibroblast activation protein (FAP). hTERT knockdown showed decreased expression of FAP and early growth response (EGR)-1, one of the transcriptional regulators of FAP in IHOK/hTERT and oral cancer cell line YD10B. Furthermore, EGR-1 knockdown in IHOK/hTERT and YD10B showed reduced invasion and reduced cathepsin D expression compared to Control-siRNA cells. Taken together, this study provides evidence that hTERT overexpression is responsible for the upregulation of the cysteine protease cathepsin D by regulating EGR-1 to activate invasiveness in cancer progression.
authors.affiliation: Oral Cancer Research Institute, Department of Oral Pathology, Yonsei University College of Dentistry, Seoul 120-752, South Korea.
authors.forename: Young-Jin
authors.initials: YJ
authors.lastname: Park
authors.affiliation: Oral Cancer Research Institute, Department of Oral Pathology, Yonsei University College of Dentistry, Seoul 120-752, South Korea; BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 120-752, South Korea.
authors.forename: Eun Kyoung
authors.initials: EK
authors.lastname: Kim
authors.affiliation: Oral Cancer Research Institute, Department of Oral Pathology, Yonsei University College of Dentistry, Seoul 120-752, South Korea.
authors.forename: Jung Yoon
authors.initials: JY
authors.lastname: Bae
authors.affiliation: Oral Cancer Research Institute, Department of Oral Pathology, Yonsei University College of Dentistry, Seoul 120-752, South Korea.
authors.forename: Sook
authors.initials: S
authors.lastname: Moon
authors.affiliation: Oral Cancer Research Institute, Department of Oral Pathology, Yonsei University College of Dentistry, Seoul 120-752, South Korea. Electronic address: jink@yuhs.ac.
authors.forename: Jin
authors.initials: J
authors.lastname: Kim
mesh_terms: D000818:Animals; D002402:Cathepsin D / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D051766:Early Growth Response Protein 1 / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009062:Mouth Neoplasms / Q000473:pathology*; D009361:Neoplasm Invasiveness; D019098:Telomerase / Q000502:physiology*
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C509186:TERT protein, human; D019098:Telomerase; D002402:Cathepsin D
keywords: Cathepsin D; Early growth response (EGR)-1; Human telomerase reverse transcriptase (hTERT); Invasion; Oral squamous cell carcinoma (OSCC)