Lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer.
BACKGROUND
Accumulating evidence indicates that the long non-coding RNA HOTAIR plays a critical role in cancer progression and metastasis. However, the overall biological role and clinical significance of HOTAIR in gastric carcinogenesis remains largely unknown.


METHODS
HOTAIR expression was measured in 78 paired cancerous and noncancerous tissue samples by real-time PCR. The effects of HOTAIR on gastric cancer cells were studied by overexpression and RNA interference approaches in vitro and in vivo. Insights of the mechanism of competitive endogenous RNAs (ceRNAs) were gained from bioinformatic analysis, luciferase assays and RNA binding protein immunoprecipitation (RIP). The positive HOTAIR/HER2 interaction was identified and verified by immunohistochemistry assay and bivariate correlation analysis.


RESULTS
HOTAIR upregulation was associated with larger tumor size, advanced pathological stage and extensive metastasis, and also correlated with shorter overall survival of gastric cancer patients. Furthermore, HOTAIR overexpression promoted the proliferation, migration and invasion of gastric carcinoma cells, while HOTAIR depletion inhibited both cell invasion and cell viability, and induced growth arrest in vitro and in vivo. In particular, HOTAIR may act as a ceRNA, effectively becoming a sink for miR-331-3p, thereby modulating the derepression of HER2 and imposing an additional level of post-transcriptional regulation. Finally, the positive HOTAIR/HER2 correlation was significantly associated with advanced gastric cancers.


CONCLUSIONS
HOTAIR overexpression represents a biomarker of poor prognosis in gastric cancer, and may confer malignant phenotype to tumor cells. The ceRNA regulatory network involving HOTAIR and the positive interaction between HOTAIR and HER2 may contribute to a better understanding of gastric cancer pathogenesis and facilitate the development of lncRNA-directed diagnostics and therapeutics against this disease.
Xiang-Hua
XH
Liu
Ming
M
Sun
Feng-Qi
FQ
Nie
Ying-Bin
YB
Ge
Er-Bao
EB
Zhang
Dan-Dan
DD
Yin
Rong
R
Kong
Rui
R
Xia
Kai-Hua
KH
Lu
Jin-Hai
JH
Li
Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, People's Republic of China. dewei@njmu.edu.cn.
Wei
W
De
Ke-Ming
KM
Wang
Zhao-Xia
ZX
Wang
D000818:Animals; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009368:Neoplasm Transplantation; D062085:RNA, Long Noncoding / Q000235:genetics* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis; D059016:Tumor Microenvironment
D014408:Biomarkers, Tumor; D035683:MicroRNAs; D062085:RNA, Long Noncoding; D018719:Erb-b2 Receptor Tyrosine Kinases; C561566:HOTAIR long untranslated RNA, human; C544460:MIRN331 microRNA, human; C508053:ERBB2 protein, human