Hypoxia-sensitive Long Noncoding RNA CASC15 Promotes Lung Tumorigenesis by Regulating the SOX4/β-catenin Axis

Abstract

Background: Accumulating evidence has demonstrated that long non-coding RNAs (lncRNAs) are involved in the hypoxia-related cancer process and play pivotal roles in enabling malignant cells to survive under hypoxic stress. However, the molecular crosstalk between lncRNAs and hypoxia signaling cascades in non-small cell lung cancer (NSCLC) remains largely elusive. Methods: Firstly, we identified differentially expressed lncRNA cancer susceptibility candidate 15 (CASC15) as associated with NSCLC based on bioinformatic data. The clinical significance of CASC15 in lung cancer was investigated by Kaplan-Meier survival analysis. Then, we modulated CASC15 expression in NSCLC cell lines by RNAi. CCK-8 and transwell assays were carried out to examine the effects of CASC15 on proliferation and migration of NSCLC cells. Upstream activator and downstream targets of CASC15 were validated by luciferase reporter assay, qRT-PCR, Western blotting, and chromatin immunoprecipitation (ChIP). Lastly, RNA in situ hybridization (RNA-ISH) and immunohistochemistry (IHC) were performed to confirm the genetic relationships between CASC15 and related genes in clinical samples. Results: CASC15 was highly expressed in NSCLC tissues and closely associated with poor prognosis. Loss-of-function analysis demonstrated that CASC15 was essential for NSCLC cell migration and growth. Mechanistic study revealed that CASC15 was transcriptionally activated by hypoxia signaling in NSCLC cells. Further analysis showed that hypoxia-induced CASC15 transactivation was mainly dependent on hypoxia-inducible factor 1α (HIF-1α) and hypoxia response elements (HREs) located in CASC15 promoter. CASC15 promotes the expression of its chromosomally nearby gene, SOX4. Then SOX4 functions to stabilize β-catenin protein, thereby enhancing the proliferation and migration of NSCLC cells. HIF-1α/CASC15/SOX4/β-catenin pathway was activated in a substantial subset of NSCLC patients. Conclusions: HIF-1α/CASC15/SOX4/β-catenin axis plays an essential role in the development and progression of NSCLC. The present work provides new evidence that lncRNA CASC15 holds great promise to be used as novel biomarkers for NSCLC. Blocking the HIF-1α/CASC15/SOX4/β-catenin axis can serve as a potential therapeutic strategy for treating NSCLC.

LncRNA CASC15, MiR-23b Cluster and SMAD3 form a Novel Positive Feedback Loop to promote Epithelial-Mesenchymal Transition and Metastasis in Ovarian Cancer

“…Recently, a novel oncogenic lncRNA, CASC15, is identified in various cancers such as basal cell [13], hepatic [14,15] and tongue squamous cell carcinoma [16], as well as cervical [17], breast [18], melanoma [19][20][21], gastric [22,23], colon [24], lung [25] and ovarian [26] cancer. Nevertheless, previously published studies on the effect of lncRNA CASC15 in ovarian cancer [26,27] are not consistent.…”

The Role of cis- and trans-Acting RNA Regulatory Elements in Leukemia

“…Through binding with DNA, RNA, and proteins in the nucleus and cytoplasm, lncRNAs influence gene expression epigenetically, co-transcriptionally, and post-transcriptionally, acting as oncogenes [88][89][90][91][92][93][94] or tumor suppressors [95][96][97][98][99][100] in cancer, Figure 1, Table 1.…”

“…Through binding with DNA, RNA, and proteins in the nucleus and cytoplasm, lncRNAs influence gene expression epigenetically, co-transcriptionally, and post-transcriptionally, acting as oncogenes [88][89][90][91][92][93][94] or tumor suppressors [95][96][97][98][99][100] in cancer, Figure 1, Table 1. long intergenic non-coding RNAs (XIST, HOTTIP, ARIEL, LUNAR1 and others) interact with Polycomb complexes and other adapter proteins, form connections between transcriptional regulators and distal DNA sequences through DNA looping; lncRNAs transcribed from antisense to protein-coding genes DNA strands, e.g., AS-RBM15, PU.1-AS, regulate expression of these genes posttranscriptionally (d); both transcriptional and posttranscriptional mechanisms of action were described for some lncRNAs, e.g., HOTAIR, HOTAIRM1, UCA1, that regulate gene expression in their genomic locus (acting in cis), and distal genomic regions (acting in trans).…”

Integrated analysis of hypoxia-associated lncRNA signature to predict prognosis and immune microenvironment of lung adenocarcinoma patients

“…Under hypoxia conditions, AC020978 was proved to be induced in lung cancer cells and facilitate tumor proliferation and glycolytic metabolism through PKM2/HIF axis [16]. Sun et al reported that CASC15 might be sensitive to hypoxia and enhance cancer cell viability [17]. However, the features of prognostic markers of lung adenocarcinoma based on hypoxiaassociated lncRNAs have not been studied.…”