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ARNTL2 knockdown suppressed the invasion and migration of colon carcinoma: decreased SMOC2-EMT expression through inactivation of PI3K/AKT pathway.

ABSTRACT: ARNTL2 is a transcriptional activator implicated in the molecular clock feedback system and is overexpressed in some malignant tumors. This study aimed to detect the effects of ARNTL2 knockdown by siRNA on the proliferation and invasion of colon carcinoma and clarify the molecular mechanisms of ARNTL2 in the development of colon carcinoma (CC). The CC microarray dataset GSE50760 was downloaded from the Gene Expression Omnibus (GEO) database. The expression levels of ARNTL2 in CC tissues and cancer cells were analyzed by immunohistochemistry and western blot, respectively. The knockdown of ARNTL2 expression was induced by RNA interference in colon cancer cells. The proliferation was detected by Cell Counting Kit-8 and clonal formation assays. The invasion and migration in vitro were detected by wound healing and transwell assays. Besides, a tumorigenicity test in the nude mice was performed to confirm whether ARNTL2 expression promoted the proliferation and invasion of CC cells. Furthermore, the expression of epithelial-mesenchymal transition (EMT) and PI3K/AKT signaling pathway-related factors were analyzed by western blot. Results showed that bioinformatics analysis found that ARNTL2 was upregulated in CC tissues. ARNTL2 was highly expressed in tissues and CC cells. Knockdown of ARNTL2 inhibited CC cells viability, colony formation, migration activity and reduced the size of tumors in the nude mice. Moreover, knockdown of ARNTL2 suppressed the expression of SMOC2, which may be the target gene of ARNTL2, and simultaneously inhibited the expression of EMT and PI3K/AKT signaling pathway-related factors. Taken together, downregulation of ARNTL2 could suppress CC cell proliferation and migration via SMOC2-EMT through inactivation of PI3K/AKT signaling pathway.

SUBMITTER: Lu M

PROVIDER: S-EPMC7191172 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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ARNTL2 knockdown suppressed the invasion and migration of colon carcinoma: decreased SMOC2-EMT expression through inactivation of PI3K/AKT pathway.

Lu Min M Huang Liyun L Tang Yinli Y Sun Tao T Li Jingyu J Xiao Sha S Zheng Xiangtao X Christopher Odong O Mao Hua H

American journal of translational research 20200415 4

ARNTL2 is a transcriptional activator implicated in the molecular clock feedback system and is overexpressed in some malignant tumors. This study aimed to detect the effects of ARNTL2 knockdown by siRNA on the proliferation and invasion of colon carcinoma and clarify the molecular mechanisms of ARNTL2 in the development of colon carcinoma (CC). The CC microarray dataset GSE50760 was downloaded from the Gene Expression Omnibus (GEO) database. The expression levels of ARNTL2 in CC tissues and canc ...[more]

PMID: 32355542

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Project description:Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) is the ninth member of the proprotein convertase family that regulates lipoprotein homeostasis and altered PCSK9 expression was reportedly associated with tumor development and progression. This study assessed PCSK9 expression and functions in human colon cancer and then explored the underlying molecular events. Methods Colon cancer tissues were utilized for analysis of PCSK9 expression for association with clinicopathological factors from patients by immunohistochemistry assay. Manipulation of PCSK9 expression was assessed in vitro and in vivo for colon cancer cell proliferation, migration, and invasion using cell viability CCK-8, Transwell tumor cell migration and invasion, and wound-healing assays. Next, proteomic analysis, Western blot, qRT-PCR and Flow cytometry were conducted to assess downstream targets and tumor cell-derived PCSK9 action on macrophage polarization. Results PCSK9 expression was upregulated in colon cancer tissues versus the normal tissues, and associated with advanced tumor pathological grade. Knockdown of PCSK9 expression reduced colon cancer cell proliferation, migration, and invasion and suppressed tumor metastasis in vivo. PCSK9 directly or indirectly upregulated Snail 1 and in turn to downregulate E-cadherin expression, but upregulate N-cadherin and MMP9 levels and thereafter, to induce colon cancer cell epithelial-mesenchymal transition (EMT) process and activated PI3K/AKT signaling. However, PCSK9 overexpression showed the inverse effects on colon cancer cells. Knockdown of PCSK9 expression inhibited M2 macrophage polarization, but also promoted M1 macrophage polarization by reduction of lactate, protein lactylation and macrophage migration inhibitory factor (MIF) levels. Conclusion PCSK9 played an important role in the progression and metastasis of colon cancer by regulation of tumor cell EMT and PI3K/AKT signaling and in the phenotypic polarization of macrophages by mediating MIF and lactate levels. Targeting PCSK9 expression or activity could be used to effectively control colon cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-022-02477-0.

Dataset Information

ARNTL2 knockdown suppressed the invasion and migration of colon carcinoma: decreased SMOC2-EMT expression through inactivation of PI3K/AKT pathway.

Publications

ARNTL2 knockdown suppressed the invasion and migration of colon carcinoma: decreased SMOC2-EMT expression through inactivation of PI3K/AKT pathway.

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