Functional Role of a Novel Long Noncoding RNA TTN-AS1 in Esophageal Squamous Cell Carcinoma Progression and Metastasis.

Purpose: Emerging studies demonstrate that long noncoding RNAs (lncRNA) participate in the regulation of various cancers. In the current study, a novel lncRNA-TTN-AS1 has been identified and explored in esophageal squamous cell carcinoma (ESCC).Experimental Design: To discover a new regulatory circuitry in which RNAs crosstalk with each other, the transcriptome of lncRNA-miRNA-mRNA from ESCC and adjacent nonmalignant specimens were analyzed using multiple microarrays and diverse bioinformatics platforms. The functional role and mechanism of a novel lncRNA-TTN-AS1 were further investigated by gain-of-function and loss-of-function assays in vivo and in vitro An ESCC biomarker panel, consisting of lncRNA-TTN-AS1, miR-133b, and FSCN1, was validated by qRT-PCR and in situ hybridization using samples from 148 patients.Results:lncRNA-TTN-AS1 as an oncogene is highly expressed in ESCC tissues and cell lines, and promotes ESCC cell proliferation and metastasis. Mechanistically, lncRNA-TTN-AS1 promotes expression of transcription factor Snail1 by competitively binding miR-133b, resulting in the epithelial-mesenchymal transition (EMT) cascade. Moreover, lncRNA-TTN-AS1 also induces FSCN1 expression by sponging miR-133b and upregulation of mRNA-stabilizing protein HuR, which further promotes ESCC invasion cascades. We also discovered and validated a clinically applicable ESCC biomarker panel, consisting of lncRNA-TTN-AS1, miR-133b, and FSCN1, that is significantly associated with overall survival and provides additional prognostic evidence for ESCC patients.Conclusions: As a novel regulator, lncRNA-TTN-AS1 plays an important role in ESCC cell proliferation and metastasis. The lncRNA-TTN-AS1/miR133b/FSCN1 regulatory axis provides bona fide targets for anti-ESCC therapies. Clin Cancer Res; 24(2); 486-98. ©2017 AACR.

Lin C ，Zhang S ，Wang Y ，Wang Y ，Nice E ，Guo C ，Zhang E ，Yu L ，Li M ，Liu C ，Hu L ，Hao J ，Qi W ，Xu H ... -  《-》

LncRNA MNX1-AS1 promotes progression of esophageal squamous cell carcinoma by regulating miR-34a/SIRT1 axis.

Long non-coding RNAs (lncRNAs) are powerful factors influencing the tumorigenesis and metastasis of multiple carcinomas. LncRNA MNX1-AS1 plays critical roles in the progression of tumor formation according to recent research, while its roles in esophageal squamous cell carcinoma (ESCC) remains unknown. The expression levels of lncRNA MNX1-AS1 were examined in ESCC tissues by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). The role of lncRNA MNX1-AS1 was performed by WST-1 proliferation assays, migration and invasion assays. Besides, the molecular mechanism of lncRNA MNX1-AS1 was verified by online bioinformatics, qRT-PCR and rescue assays. MNX1-AS1 was signifcantly upregulated in ESCC tissues. It was conformed that high MNX1-AS1 expression was associated with ESCC lymph node metastasis. Moreover, we found that knockdown of MNX1-AS1 apparently suppressed the cell proliferation, migration, and invasion capacity. Flow cytometry analysis showed MNX1-AS1 regulated ESCC cell cycle and apoptosis progression. Mechanism analysis revealed that miR-34a inhibitor could rescue the influence of inhibiting MNX1-AS1 on ESCC cells migration by serving as competing endogenous RNA (ceRNAs). Furthermore, we found that miR-34a specifically targeted SIRTI. Taken together, we demonstrated that lncRNA MNX1-AS1/miR-34a/SIRT1 regulatory axis could play an important role in ESCC progression, and MNX1-AS1 may act as a novel potential biomarker for esophageal squamous cell carcinoma.

Chu J ，Li H ，Xing Y ，Jia J ，Sheng J ，Yang L ，Sun K ，Qu Y ，Zhang Y ，Yin H ，Wan J ，He F ... -  《-》

Long non-coding RNA TTN-AS1 facilitates tumorigenesis of papillary thyroid cancer through modulating the miR-153-3p/ZNRF2 axis.

Long non-coding RNAs (lncRNAs) are crucial modulators in the tumorigenesis of numerous cancers, including papillary thyroid cancer (PTC). However, it is unclear whether lncRNA TTN antisense RNA 1 (TTN-AS1) can regulate PTC progression. The present study aimed to reveal the mechanism and function of TTN-AS1 in PTC. TTN-AS1 expression in 92 pairs PTC tissues and four PTC cells was measured via a quantitative reverse transcriptase-polymerase chain reaction assay. The relationship of TTN-AS1 expression and clinical pathological features of PTC patients was analyzed using a chi-squared test. The biofunction of TTN-AS1 in PTC was identified by loss or gain-of-function assays. Based on bioinformatics analysis and mechanism experiments, the molecular mechanism of TTN-AS1 was analyzed and identified. A high level of TTN-AS1 was observed in PTC tissues and cells. The expression level of TTN-AS1 is possibly associated with lymphatic metastasis, TNM stage and the overall survival of PTC patients. Functionally, TTN-AS1 knockdown inhibited cell proliferation, migration, invasion and epithelial-mesenchymal transition in PTC, whereas overexpression of TTN-AS1 led to the opposite results. Mechanistically, TTN-AS1 acted as a competing endogenous RNA by sponging microRNA-153-3p (miR-153-3p) to elevate zinc and ring finger 2 (ZNRF2) expression. Additionally, a high level of TTN-AS1 in PTC was closely correlated with the activity of the phosphoinositide 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway. The findings obtained in the present study indicate that TTN-AS1 facilitated PTC progression by regulating the miR-153-3p/ZNRF2 axis and activating the PI3K/Akt/mTOR pathway.

Cui Z ，Luo Z ，Lin Z ，Shi L ，Hong Y ，Yan C ... -  《-》

LncRNA TTN-AS1 promotes the progression of cholangiocarcinoma via the miR-320a/neuropilin-1 axis.

Zhu H ，Zhai B ，He C ，Li Z ，Gao H ，Niu Z ，Jiang X ，Lu J ，Sun X ... -  《Cell Death & Disease》

Long noncoding RNA TTN-AS1 facilitates tumorigenesis and metastasis by maintaining TTN expression in skin cutaneous melanoma.

Wang Y ，Li D ，Lu J ，Chen L ，Zhang S ，Qi W ，Li W ，Xu H ... -  《Cell Death & Disease》