title: Epithelial mesenchymal transition is required for acquisition of anoikis resistance and metastatic potential in adenoid cystic carcinoma.
abstract: Human adenoid cystic carcinoma (ACC) is characterized by diffused invasion of the tumor into adjacent organs and early distant metastasis. Anoikis resistance and epithelial mesenchymal transition (EMT) are considered prerequisites for cancer cells to metastasize. Exploring the relationship between these processes and their underlying mechanism of action is a promising way to better understand ACC tumors. We initially established anoikis-resistant sublines of ACC cells; the variant cells revealed a mesenchymal phenotype through Slug-mediated EMT-like transformation and displayed enhanced metastatic potential both in vitro and in vivo. Suppression of EMT by knockdown of Slug significantly impaired anoikis resistance, migration, and invasion of the variant cells. With overexpression of Slug and Twist, we determined that induction of EMT in normal ACC cells could prevent anoikis, albeit partially. These findings strongly suggest that EMT is indispensable in anoikis resistance, at least in ACC cells. Furthermore, we found that the EGFR/PI3K/Akt pathway acts as the common regulator for EMT-like transformation and anoikis resistance, as confirmed by their specific inhibitors. Gefitinib and LY294003 restored the sensibilities of anoikis-resistant cells to anoikis and simultaneously impaired their metastatic potential. In addition, the results from our in vivo model of metastasis suggest that pretreatment with gefitinib promotes mouse survival by alleviating pulmonary metastasis. Most importantly, immunohistochemistry of human ACC specimens showed a correlation between the overexpression of Slug and EGFR staining. This study has demonstrated that Slug-mediated EMT-like transformation is required by human ACC cells to achieve anoikis resistance and their metastatic potential. Targeting the EGFR/PI3K/Akt pathway holds potential as a preventive strategy against distant metastasis of ACC.
authors.affiliation: The State Key Laboratory Breeding Base of Basic Science of Stomatology and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Jia
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Jian-Ying
authors.initials: JY
authors.lastname: Liu
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Hao-Yan
authors.initials: HY
authors.lastname: Zhong
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.forename: Yu
authors.initials: Y
authors.lastname: Cai
authors.forename: Jia-Li
authors.initials: JL
authors.lastname: Zhang
authors.forename: Yi-Fang
authors.initials: YF
authors.lastname: Zhao
mesh_terms: D000818:Animals; D023102:Anoikis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D003528:Carcinoma, Adenoid Cystic / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D012468:Salivary Gland Neoplasms / Q000378:metabolism* / Q000473:pathology*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib