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Norepinephrine-CREB1-miR-373 axis promotes progression of colon cancer.

ABSTRACT: The adrenergic system contributes to the stress-induced onset and progression of cancer. Adrenergic fibers are the primary source of norepinephrine (NE). The underlying mechanisms involved in NE-induced colon cancer remain to be understood. In this study, we describe the function and regulatory network of NE in the progression of colon cancer. We demonstrate that NE-induced phosphorylation of cAMP response element-binding protein 1 (CREB1) promotes proliferation, migration, and invasion of human colon cancer cells. The downstream effector of NE, CREB1, bound to the promoter of miR-373 and transcriptionally activated its expression. miR-373 expression was shown to be necessary for NE-induced cell proliferation, invasion, and tumor growth. We confirmed that proliferation and invasion of colon cancer cells are regulated in vitro and in vivo by miR-373 through targeting of the tumor suppressors TIMP2 and APC. Our data suggest that NE promotes colon cancer cell proliferation and metastasis by activating the CREB1-miR-373 axis. The study of this novel signaling axis may provide mechanistic insights into the neural regulation of colon cancer and help in the design of future clinical studies on stress biology in colorectal cancer.

SUBMITTER: Han J

PROVIDER: S-EPMC7191185 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Norepinephrine-CREB1-miR-373 axis promotes progression of colon cancer.

Han Jia J Jiang Qiuyu Q Ma Ruili R Zhang Huahua H Tong Dongdong D Tang Kaijie K Wang Xiaofei X Ni Lei L Miao Jiyu J Duan Baojun B Yang Yang Y Chen Yanke Y Wu Fei F Han Jiming J Wang Mengchang M Hou Ni N Huang Chen C

Molecular oncology 20200313 5

The adrenergic system contributes to the stress-induced onset and progression of cancer. Adrenergic fibers are the primary source of norepinephrine (NE). The underlying mechanisms involved in NE-induced colon cancer remain to be understood. In this study, we describe the function and regulatory network of NE in the progression of colon cancer. We demonstrate that NE-induced phosphorylation of cAMP response element-binding protein 1 (CREB1) promotes proliferation, migration, and invasion of human ...[more]

PMID: 32118353

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Project description:BackgroundBreast cancer (BC) is a prevalent malignancy with complex etiology and varied clinical behavior. Long non-coding RNAs (lncRNAs) have emerged as key regulators in cancer progression, including BC. Among these, lncRNA TDRKH-AS1 has been implicated in several cancers, but its role in BC remains unclear.MethodsWe conducted a comprehensive investigation to elucidate the role of TDRKH-AS1 in BC. Clinical samples were collected from BC patients, and BC cell lines were cultured. Bioinformatics analysis using the starBase database was carried out to assess TDRKH-AS1 expression levels in BC tissue samples. Functional experiments, including knockdown, colony formation, CCK-8, Transwell, and wound-healing assays, were conducted to determine the role of TDRKH-AS1 in BC cell proliferation and invasion. Luciferase reporter and RIP assays were used to examine the interactions between TDRKH-AS1 and miR-134-5p. In addition, the downstream target gene of miR-134-5p, cAMP response element-binding protein 1 (CREB1), was identified and studied using various methods, including RT-qPCR, immunoprecipitation, and rescue experiments. In vivo experiments using mouse tumor xenograft models were conducted to examine the role of TDRKH-AS1 in BC tumorigenesis.ResultsTDRKH-AS1 was found to be significantly upregulated in BC tissues and cell lines. High TDRKH-AS1 expression correlated with advanced BC stages and worse patient outcomes. Knockdown of TDRKH-AS1 led to decreased BC cell proliferation and invasion. Mechanistically, TDRKH-AS1 acted as a sponge for miR-134-5p, thereby reducing the inhibitory effects of miR-134-5p on CREB1 expression. Overexpression of CREB1 partially rescued the effects of TDRKH-AS1 knockdown in BC cells. In vivo studies further confirmed the tumor-promoting role of TDRKH-AS1 in BC.ConclusionsOur study unveiled a novel regulatory axis involving TDRKH-AS1, miR-134-5p, and CREB1 in BC progression. TDRKH-AS1 functioned as an oncogenic lncRNA by promoting BC cell proliferation and invasion through modulation of the miR-134-5p/CREB1 axis. These findings highlighted TDRKH-AS1 as a potential diagnostic biomarker and therapeutic target for BC treatment.

Project description:BackgroundLncRNAs act as functional regulators in tumor progression through interacting with various signaling pathways in multiple types of cancer. However, the effect of LINC02418 on colorectal cancer (CRC) progression and the underling mechanisms remain unclear.MethodsLncRNA expression profile in CRC tissues was investigated by the TCGA database. The expressional level of LINC02418 in CRC patients was determined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Kaplan-Meier analyses was used to investigate the correlation between LINC02418 and overall survival (OS) of CRC patients. Cell proliferative, migratory and invasive abilities were detected by CCK-8 assays, colony formation assays and trans-well assays in HCT116 and LoVo cells which were stably transduced with sh-LINC02418 or sh-NC. The binding between LINC02418 and miR-34b-5p, and the interaction between miR-34b-5p and BCL2 were determined by dual-luciferase assays. Western blot experiments were conducted to further explore the effect of miR-34b-5p on BCL2 signaling pathway. Rescue experiments were performed to uncover the role of LINC02418/miR-34b-5p/BCL2 axis in CRC progression.ResultsLINC02418 was upregulated in human colon cancer samples when compared with adjacent tissue, and its high expressional level correlated with poor prognosis of CRC patients. LINC02418 promoted cancer progression by enhancing tumor growth, cell mobility and invasiveness of colon cancer cells. Additionally, LINC02418 could physically bind to miR-34b-5p and subsequently affect BCL2 signaling pathway. Down-regulation of LINC02418 reduced cell proliferation, while transfection of miR-34b-5p inhibitor or BCL2 into LINC02418-silenced CRC cells significantly promoted CRC cells growth.ConclusionsLINC02418 was upregulated in human CRC samples and could be used as the indicator for prediction of prognosis. LINC02418 acted as a tumor driver by negatively regulating cell apoptosis through LINC02418/miR-34b-5p/BCL2 axis in CRC.

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Norepinephrine-CREB1-miR-373 axis promotes progression of colon cancer.

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Norepinephrine-CREB1-miR-373 axis promotes progression of colon cancer.

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