RETRACTED ARTICLE: Down-regulated lncRNA DLX6-AS1 inhibits tumorigenesis through STAT3 signaling pathway by suppressing CADM1 promoter methylation in liver cancer stem cells

Abstract

Background Liver cancer stem cells (LCSCs) are a small subset of cells characterized by unlimited self-renewal, cell differentiation, and uncontrollable cellular growth. LCSCs are also resistant to conventional therapies and are thus believed to be held responsible for causing treatment failure of hepatocellular carcinoma (HCC). It has been recently found that long non-coding RNAs (lncRNAs) are important regulators in HCC. This present study aims to explore the underlying mechanism of how lncRNA DLX6-AS1 influences the development of LCSCs and HCC. Methods A microarray-based analysis was performed to initially screen differentially expressed lncRNAs associated with HCC. We then analyzed the lncRNA DLX6-AS1 levels as well as CADM1 promoter methylation. The mRNA and protein expression of CADM1, STAT3, CD133, CD13, OCT-4, SOX2, and Nanog were then detected. We quantified our results by evaluating the spheroid formation, proliferation, and tumor formation abilities, as well as the proportion of tumor stem cells, and the recruitment of DNA methyltransferase (DNMT) in LCSCs when lncRNA DLX6-AS1 was either overexpressed or silenced. Results LncRNA DLX6-AS1 was upregulated in HCC. The silencing of lncRNA DLX6-AS1 was shown to reduce and inhibit spheroid formation, colony formation, proliferation, and tumor formation abilities, as well as attenuate CD133, CD13, OCT-4, SOX2, and Nanog expression in LCSCs. Furthermore, downregulation of lncRNA DLX6-AS1 contributed to a reduction in CADM1 promoter methylation via suppression of DNMT1, DNMT3a, and DNMT3b in LCSCs and inactivating the STAT3 signaling pathway. Conclusion This study demonstrated that down-regulated lncRNA DLX6-AS1 may inhibit the stem cell properties of LCSCs through upregulation of CADM1 by suppressing the methylation of the CADM1 promoter and inactivation of the STAT3 signaling pathway. Electronic supplementary material The online version of this article (10.1186/s13046-019-1239-3) contains supplementary material, which is available to authorized users.

LncRNA DLX6-AS1 as a potential molecular biomarker in the clinicopathology and prognosis of various cancers: a meta-analysis

“…A total of 23 articles were identified for full review, 11 of which were excluded due to lack of necessary data or in vitro studies. Finally, the remaining 12 articles [8,9,11,[14][15][16][17][18][19][20][21][22] were included in this meta-analysis. These eligible studies were published between 2017 and 2019, and covered a total of 841 patients.…”

ceRNA Network Development and Tumour-infiltrating Immune Cell Analysis in Metastatic Breast Cancer of Bone

“…Recently, an increasing number of studies show that aberrant lncrnas expression leads to the development of many kinds of malignant tumours, including breast cancer [12][13][14][15][16][17][18]. As a kind of lncrnas, dlx6-as1 is believed to be carcinogenic by regulating the progression of renal cell carcinoma, liver cell carcinoma, glioma, pancreatic cancer and lung adenocarcinoma [19][20][21][22][23][24][25][26]. Normal brain tissue has a high expression of DLX6-AS1, which is involved in the development regulation [24][25][26].…”

“…Normal brain tissue has a high expression of DLX6-AS1, which is involved in the development regulation [24][25][26]. In recent years, it has been found that dlx6-as1 is abnormally expressed in a variety of tumour tissues and is closely related to a poor clinical outcome [19][20][21][22][23][24][25][26]. However, the molecular mechanisms of dlx6-as1 and how it contributes to the pathogenesis of breast cancer are still unclear.…”

“…Zhao et al demonstrated signi cant upregulation of dlx6-as1 in breast cancer tissues and cell lines [27]. Furthermore, high dlx6-as1 expression is linked to poor outcome regarding tumour size, lymph node metastasis, TNM stage, and survival of breast cancer patients [19][20][21][22][23][24][25][26][27]. SiRNA knockout of dlx6-as1 showed a reduction in proliferation, apoptosis, invasion, migration, and epithelial-mesenchymal transition (EMT) of breast cancer cells [25][26][27].…”

<p>lncRNA DLX6-AS1 Promotes Proliferation of Laryngeal Cancer Cells by Targeting the miR-26a/TRPC3 Pathway</p>

“…Additionally, lncRNA DLX6-AS1 has been shown to promote tumor growth by modulating HSP90 expression in bladder cancer, 12 regulating cell invasion in cervical cancer 13 and epithelial-mesenchymal transition in gastric cancer, 14 and promoting tumorigenesis through the STAT3 signaling pathway in liver cancer stem cells. 15 However, the role of DLX6-AS1 in laryngeal cancer has not been defined.…”