title: Hypoxia-inducible lncRNA-AK058003 promotes gastric cancer metastasis by targeting γ-synuclein.
abstract: Hypoxia has been implicated as a crucial microenvironmental factor that induces cancer metastasis. We previously reported that hypoxia could promote gastric cancer (GC) metastasis, but the underlying mechanisms are not clear. Long noncoding RNAs (lncRNAs) have recently emerged as important regulators of carcinogenesis that act on multiple pathways. However, whether lncRNAs are involved in hypoxia-induced GC metastasis remains unknown. In this study, we investigated the differentially expressed lncRNAs resulting from hypoxia-induced GC and normoxia conditions using microarrays and validated our results through real-time quantitative polymerase chain reaction. We found an lncRNA, AK058003, that is upregulated by hypoxia. AK058003 is frequently upregulated in GC samples and promotes GC migration and invasion in vivo and in vitro. Furthermore, AK058003 can mediate the metastasis of hypoxia-induced GC cells. Next, we identified γ-synuclein (SNCG), which is a metastasis-related gene regulated by AK058003. In addition, we found that the expression of SNCG is positively correlated with that of AK058003 in the clinical GC samples used in our study. Furthermore, we found that the SNCG gene CpG island methylation was significantly increased in GC cells depleted of AK058003. Intriguingly, SNCG expression is also increased by hypoxia, and SNCG upregulation by AK058003 mediates hypoxia-induced GC cell metastasis. These results advance our understanding of the role of lncRNA-AK058003 as a regulator of hypoxia signaling, and this newly identified hypoxia/lncRNA-AK058003/SNCG pathway may help in the development of new therapeutics.
authors.affiliation: Department of Oncology, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Xi'an 710038, China.
authors.forename: Yafang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032,China.
authors.forename: Xiangqiang
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032,China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032,China.
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of thoracic surgery, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Xi'an 710038, China.
authors.forename: Yongan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032,China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Jin
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032,China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032,China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032,China.
authors.forename: Jiaming
authors.initials: J
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032,China.
authors.forename: Hao
authors.initials: H
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032,China.
authors.forename: Yongzhan
authors.initials: Y
authors.lastname: Nie
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032,China.
authors.forename: Kaichun
authors.initials: K
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Cancer Biology & Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032,China.
authors.forename: Daiming
authors.initials: D
authors.lastname: Fan
authors.affiliation: Department of Oncology, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Xi'an 710038, China. Electronic address: cnxazhl@163.com.
authors.forename: Helong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Tangdu Hospital, Fourth Military Medical University, 1 Xinsi Road, Xi'an 710038, China. Electronic address: lily123fmmu@aliyun.com.
authors.forename: Lili
authors.initials: L
authors.lastname: Liu
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D018899:CpG Islands / Q000235:genetics; D006801:Humans; D000860:Hypoxia / Q000235:genetics*; D051379:Mice; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics*; D010957:Plasmids / Q000235:genetics; D062085:RNA, Long Noncoding / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology*; D014162:Transfection; D051845:gamma-Synuclein / Q000235:genetics*
chemical_list: D009363:Neoplasm Proteins; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C104249:SNCG protein, human; D051845:gamma-Synuclein