Abstract
Colorectal cancer (CRC) is one of the most common cancers around the world and endangers human health seriously. Liver metastasis is an important factor affecting the long-term prognosis of CRC and the specific mechanism of CRLM (colorectal cancer with liver metastasis) is not fully understood. LZTS1 has been found dysregulated in many cancers, especially in CRC. Theories suggested that hypermethylation of the promoter regions of LZTS1 was responsible for LZTS1 abnormal expression in multiple malignant tumors. Although the role of LZTS1 in CRC cell proliferation has been reported, its role in CRLM remains unclear. Numerous studies reported Long non-coding RNA (lncRNA) could regulate the gene expression level by regulating gene methylation status in many tumors. However, whether there were lncRNAs could change the methylation status of LZTS1 or not in CRLM was unknown. In this study, we aimed to investigate whether there are lncRNAs can regulate the expression of LZTS1 through affecting DNA methylation in CRLM. We found that upregulated Lnc-LALC in CRC was negatively correlated with LZTS1 expression, and Lnc-LALC could regulate LZTS1 expression in both mRNA and protein level in our study. Functionally, Lnc-LALC enhanced the CRC cells metastasis ability in vitro and vivo through inhibiting the expression of LZTS1. Furthermore, the precise mechanisms exploration showed that lnc-LALC could recruit DNA methyltransferases (DNMTs) to the LZTS1 promoter by combining with Enhancer of zeste homolog 2(EZH2) and then altered the expression of LZTS1 via DNMTs-mediated DNA methylation. Collectively, our data demonstrated the important role of Lnc-LALC/ LZTS1 axis in CRLM development.
Highlights
Colorectal cancer (CRC) is one of the most common cancers worldwide
We collected 10 samples of normal intestinal epithelial tissues(N), non-metastatic paraneoplastic intestinal epithelial tissues(P), non-metastatic primary tumor tissues (CRC), and primary tumor tissues with hepatic metastatic(HM-CRC), respectively. qRT-PCR and immunohistochemistry staining indicated that Leucine zipper tumor-suppressor gene 1 (LZTS1) expression level was negatively correlated with CRC metastasis (Fig. 1A, C, D)
QRT-PCR results revealed that LZTS1 was downregulated in CRC cell lines when the NCM460 cells were used as a control (Fig. 1B)
Summary
Colorectal cancer (CRC) is one of the most common cancers worldwide. According to the data published in the Journal of Cancer in 2018, the incidence and mortality of CRC both rank third among all malignant tumors, whichLeucine zipper tumor-suppressor gene 1 (LZTS1) gene was firstly detected in esophageal cancer by microsatelliteOfficial journal of the Cell Death Differentiation AssociationZhang et al Cell Death and Disease (2021)12:224 technology in 19994. According to the data published in the Journal of Cancer in 2018, the incidence and mortality of CRC both rank third among all malignant tumors, which. Leucine zipper tumor-suppressor gene 1 (LZTS1) gene was firstly detected in esophageal cancer by microsatellite. Official journal of the Cell Death Differentiation Association. Zhang et al Cell Death and Disease (2021)12:224 technology in 19994. It is located at chromosome 8p22 and encodes a 67 kDa leucine zipper protein in the normal tissues while its expression was frequently downregulated or deficient in multiple cancers such as gastric cancer, lung cancer, and breast cancer[5,6,7]. The molecular mechanisms of LZTS1 and its methylation in CRLM remain largely unknown
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