Up-regulated miR-548k promotes esophageal squamous cell carcinoma progression via targeting long noncoding RNA-LET.

Dysregulated noncoding RNAs have been observed in diverse cancers. MIR458K is frequently amplified in esophageal squamous cell carcinoma (ESCC). However, the expression, clinical significances, and action mechanisms of miR-548k in ESCC are still unclear. In this study, we found that miR-548k is significantly up-regulated in ESCC tissues and cell lines. Up-regulated miR-548k expression is significantly correlated with advanced invasion depth, lymph node metastasis, advanced TNM stage, and poor overall survival. Gain-of- and loss-of-function assays demonstrated that miR-548k promotes the proliferation and migration of ESCC cells in vitro and tumor growth in vivo. Mechanistically, we found that miR-548k directly targets and represses the expression of long noncoding RNA-LET (lncRNA-LET), and further down-regulates p53 and up-regulates NF90. In addition, we found that lncRNA-LET is down-regulated and inversely correlated with miR-548k in ESCC. Down-regulated lncRNA-LET also indicated poor overall survival of ESCC patients. Functional assays demonstrated that lncRNA-LET inhibits the proliferation and migration of ESCC cells, and the effects of miR-548k on ESCC are dependent on the negative regulation of lncRNA-LET. In summary, our data revealed the critical roles of miR-548k-lncRNA-LET regulation axis in ESCC and suggested that the miR-548k-lncRNA-LET regulation axis may be promising prognostic biomarkers and therapeutic targets for ESCC.

Chen Z ，Lin J ，Wu S ，Xu C ，Chen F ，Huang Z ... -  《-》

An NF90/long noncoding RNA-LET/miR-548k feedback amplification loop controls esophageal squamous cell carcinoma progression.

In our previous study we have found that miR-548k has oncogenic roles in esophageal squamous cell carcinoma (ESCC) via repressing long noncoding RNA (lncRNA)-LET and further upregulating nuclear factor 90 (NF90). However, the upstream factors controlling miR-548k expression are still unknown. In this study, we found NF90 directly binds pri-miR-548k, increases the stability of pri-miR-548k, and upregulates the expression of pri-miR-548k and miR-548k. Therefore, NF90, miR-548k and lncRNA-LET forms a feedback loop. Gain-of-function and loss-of-function assays demonstrated that in accordance with the roles of miR-548k, NF90 also promotes ESCC cell proliferation and migration. Furthermore, we verified the regulatory feedback loop between NF90, miR-548k, and lncRNA-LET. We found NF90 upregulated miR-548k and downregulated lncRNA-LET. miR-548k downregulated lncRNA-LET and upregulated NF90. lncRNA-LET downregulated NF90 and miR-548k. Through the reciprocal regulations between each other, the NF90/miR-548k/lncRNA-LET feedback loop controls the expressions of NF90 targets (HIF-1α and VEGF), miR-548k targets (KLF10 and EGFR), and lncRNA-LET target (p53). Further functional assays demonstrated that activation of the NF90/miR-548k/lncRNA-LET feedback loop via simultaneously overexpressing NF90 and miR-548k and simultaneously depleting lncRNA-LET significantly promotes ESCC cell proliferation and migration in vitro and ESCC tumor growth in vivo. Targeting the NF90/miR-548k/lncRNA-LET feedback loop via simultaneously depleting NF90 and miR-548k and simultaneously overexpressing lncRNA-LET significantly inhibits ESCC cell proliferation and migration in vitro and ESCC tumor growth in vivo. In summary, our findings identified a crucial oncogenic NF90/lncRNA-LET/miR-548k feedback amplification loop, which may be promising therapeutic targets for ESCC.

Lin J ，Chen Z ，Wu S ，Huang W ，Chen F ，Huang Z ... -  《Journal of Cancer》

Long noncoding RNA H19 is up-regulated in esophageal squamous cell carcinoma and promotes cell proliferation and metastasis.

Long noncoding RNAs (lncRNAs) have been shown to play various roles in tumorigenesis, among which lncRNA H19 has been revealed as an ambivalent factor that acts as both an oncogene and a tumor suppressor in carcinogenesis. However, the exact biological role of H19 in esophageal squamous cell carcinoma (ESCC) remains to be determined. The aim of this study was to examine the expression pattern of H19 in ESCC and evaluate its biological role and clinical significance in the progression of ESCC. Expression of H19 was analyzed in 64 ESCC tissues and four ESCC cell lines by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Proliferation, cell cycle, migration, and invasion assays were performed in ESCC cell lines following knockdown of H19 to determine the biological function of H19 in the progression of ESCC both in vitro and in vivo. Western blot analysis was also performed to identify the potential mechanisms involved. H19 was highly expressed both in ESCC samples and cell lines compared with corresponding normal counterparts. The up-regulation of of H19 was significantly correlated with ESCC clinical stage and lymph node metastasis. Knockdown of H19 not only exerted inhibitory effect on tumor proliferation in vitro and in vivo, but also repressed the migratory and invasive capacity. G0/G1 phase arrest was also found in H19 knockdown cell lines. In addition, silencing of H19 up-regulated epithelial marker E-cadherin while down-regulating mesenchymal marker vimentin and metastasis-associated protein such as MMP-9. These findings indicate that H19 acts as an oncogene and promotes ESCC cell proliferation and metastasis, which may infer H19 as a marker of poor prognosis and, thus, a potential therapeutic target for treating ESCC patients.

Tan D ，Wu Y ，Hu L ，He P ，Xiong G ，Bai Y ，Yang K ... -  《-》

Exosomal lncRNA ZFAS1 regulates esophageal squamous cell carcinoma cell proliferation, invasion, migration and apoptosis via microRNA-124/STAT3 axis.

Li Z ，Qin X ，Bian W ，Li Y ，Shan B ，Yao Z ，Li S ... -  《JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH》

Long non-coding RNA-Low Expression in Tumor inhibits the invasion and metastasis of esophageal squamous cell carcinoma by regulating p53 expression.

Wang PL ，Liu B ，Xia Y ，Pan CF ，Ma T ，Chen YJ ... -  《-》