Abstract
Esophageal squamous cell carcinoma (ESCC) is the main subtype of esophageal cancer. Long noncoding RNAs (lncRNAs) are thought to play a critical role in cancer development. Recently, lncRNA CASC9 was shown to be dysregulated in many cancer types, but the mechanisms whereby this occurs remain largely unknown. In this study, we found that CASC9 was significantly upregulated in ESCC tissues, with further analysis revealing that elevated CASC9 expression was associated with ESCC prognosis and metastasis. Furthermore, we found that CASC9 knockdown significantly repressed ESCC migration and invasion in vitro and metastasis in nude mice in vivo. A microarray analysis and mechanical experiments indicated that CASC9 preferentially affected gene expression linked to ECM–integrin interactions, including LAMC2, an upstream inducer of the integrin pathway. We demonstrated that LAMC2 was consistently upregulated in ESCC and promoted ESCC metastasis. LAMC2 overexpression partially compromised the decrease of cell migration and invasion capacity in CASC9 knockdowns. In addition, we found that both CASC9 and LAMC2 depletion reduced the phosphorylation of FAK, PI3K, and Akt, which are downstream effectors of the integrin pathway. Moreover, the reduction in phosphorylation caused by CASC9 depletion was rescued by LAMC2 overexpression, further confirming that CASC9 exerts a pro-metastatic role through LAMC2. Mechanistically, RNA pull-down and RNA-binding protein immunoprecipitation (RIP) assay indicated that CASC9 could bind with the transcriptional coactivator CREB-binding protein (CBP) in the nucleus. Chromatin immunoprecipitation (ChIP) assay additionally illustrated that CASC9 increased the enrichment of CBP and H3K27 acetylation in the LAMC2 promoter, thereby upregulating LAMC2 expression. In conclusion, we demonstrate that CASC9 upregulates LAMC2 expression by binding with CBP and modifying histone acetylation. Our research reveals the prognostic and pro-metastatic roles for CASC9 in ESCC, suggesting that CASC9 could serve as a biomarker for prognosis and a target for metastasis treatment.
Highlights
We found that CASC9 was overexpressed in 88.7% (102/115) of Esophageal squamous cell carcinoma (ESCC) tissue compared to normal tissue samples (Fig. 1a)
Further analysis revealed that tumor differentiation grade, primary tumor invasion depth, lymph node metastasis, and advanced TNM stage were all positively correlated with CASC9 expression (Fig. 1b, c, d, e), which strongly suggested that CASC9 might contribute to ESCC malignance, metastasis
We show that CASC9 was significantly upregulated in ESCC tissues, and high CASC9 expression correlated with a deeper primary invasion depth, positive lymph node metastasis, and advanced TNM stage, suggesting that CASC9 can be a strong predictor for ESCC metastasis and prognosis
Summary
Esophageal cancer (EC) is one of the most aggressive cancer types with an increasing incidence worldwide [1]. Esophageal squamous cell carcinoma (ESCC) is the predominant histological cancer type, accounting for ~80% of EC cancers [2]. Despite intensive clinical efforts using multiple therapeutic approaches, the overall 5-year survive rate remains at 15–25% due to a combination of both local invasion and distant metastasis [3]. Many patients with esophageal cancer already exhibit metastasis at diagnosis, even when tumors are superficial. Ensuing complications from tumor metastasis account for the majority of cancerassociated deaths [4]. Many studies have revealed that alterations in gene expression, cytokine secretion, Official journal of the Cell Death Differentiation Association
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