Elsevier

Cellular Signalling

Volume 61, September 2019, Pages 86-92
Cellular Signalling

Estrogen receptor alpha regulates the Wnt/β-catenin signaling pathway in colon cancer by targeting the NOD-like receptors

https://doi.org/10.1016/j.cellsig.2019.05.009Get rights and content

Highlights

  • NLRs and ERs were differentially expressed in different tumor tissues.

  • Discrepant expressions of NLRs and ERs play an important role in colon tumorigenesis and progression.

  • ER regulates the Wnt/β-catenin signaling pathway in the colon.

  • ERα regulates the Wnt/β-catenin signaling pathway by targeting the NLRP3 in colon cancer.

Abstract

It has been reported that estrogen receptors (ERs) participate in carcinogenesis by directly regulating NOD-like receptors (NLRs). However, the expression profiles of ERs and NLRs in tumor and the ER-NLR regulated signaling pathway are not clear. In this study, we summarized gene expression profiles of ERs and NLRs across normal and tumor tissue by comprehensive data mining. Then we explored the ER-NLR regulated signaling pathway by RNA sequencing (RNA-seq). The results showed that the NLRs and ERs were differentially expressed in different neoplasm tissues. Such expression discrepancies might influence inflammatory regulation and tumorigenesis. Importantly, we identified that ER-NLR regulate Wnt/β-catenin pathway in colon cancer. Taking colon adenocarcinoma (COAD) as example, we found that Wnt2b/LRP8/Dvl1/Axin2/GSK3a/APC/β-catenin genes were differentially expressed in ER−/− mouse colon tissue and colon cancer cells. The selective ERα antagonist could significantly decrease Wnt2b/LRP8/Dvl1 expression, increase destruction complex (Axin2/GSK3a/APC) expression, and promote degradation of β-catenin in colon carcinoma cell by inhibited NLRP3 expression. In short, the research demonstrates that NLRs are potential biomarkers for cancer, and ERs can regulate the Wnt/β-catenin signaling pathway in cancer by targeting the NLRs. Our results provide a possible signaling pathway in which ER-NLR is correlated with Wnt/β-catenin.

Introduction

NOD-like receptors (NLRs) are a newly discovered family of pattern recognition receptors (PRRs) which play a key role in immune regulation of innate immunity and adaptive immunity [1]. NLRs contain 3 domains, including N-terminal signal transduction domain for protein-protein interaction, central NACHT domain for oligomerization, and C-terminal ligand recognition domain with leucine-rich repeats. The leucine-rich repeats domain also acts as a repressor of NLR signaling by masking the N-terminal domain in the absence of ligand stimulation [2]. As reported, mammalian NLRs can be classified into four types based on their N-terminal domain: CIITA, NAIP, NLRCs (including NOD1, NOD2, NLRC3–5, NLRX1), and NLRPs (including NLRP1-NLRP14) [3]. Due to the active role of NLRs in regulating pro-inflammatory signals and recruiting the adaptive arm of the immune system, NLRs have been reported to influence disease outcomes and tumorigenesis. For instance, NLRP3 is involved in lymphangiogenesis and metastasis [4]. CIITA plays an important role in lymphoid cancers [5]. NLRC5 can regulate cell proliferation, migration, and invasion by targeting the Wnt/β-catenin signaling pathway in hepatocellular carcinoma [6]. However, expression profiles of NLRs across normal and tumor tissue have not been researched.

Nuclear receptors (NRs), acting as transcription factors, can bind to DNA and influence the adjacent genes expression. It has been reported that NOD proteins, such as NOD1, NOD2, and NOD4, are positively related to NRs [7]. Therefore, it is obvious that the regulation of NRs plays a key role in NLR-related neoplasms. ERs (including ERα and ERβ) are members of the NRs. It has been reported that estrogen can attenuate local inflammasome activation during spinal cord injury and suppress hepatocellular carcinoma cells through upregulation of the NLRP3 inflammasome-mediated with ERβ [8,9]. In our previous study, we have demonstrated that ERs participate in carcinogenesis by directly regulating NLRs in colon cancer cells [10]. However, the downstream regulatory pathway of ER-NLR in colon cancer remained unknown. Considering the important role of ERs and NLRs in neoplasm, further research on this signaling pathway may benefit neoplasm prevention and therapy. In this research, based on data mining, we found that NLRs and ERs were differentially expressed in neoplasm tissues. Taking COAD as an example, the mRNA of both NLRP3 and ERα were significantly increased in tumor tissues relative to the matched normal tissues. Furthermore, a possible signaling pathway in which ER-NLR was related with Wnt/β-catenin was provided.

Section snippets

Expression profiles of NLRs in different neoplasm tissues

The expression profiles of NLRs in different neoplasm tissues were acquired based on the expression values of each gene in RNA-SEQv2 of the Cancer Genome Atlas (TCGA) Data Portal (https://tcga-data.nci.nih.gov/tcga/) according to a previous method [11]. The NLRP3 and ERα expression profiles in colon adenocarcinoma tissues from Gene Expression across Normal and Tumor tissue database (http://medical-genome.kribb.re.kr/GENT/search/search.php), The Human Protein Atlas database (//www.proteinatlas.org/

NLRs and ERs are differentially expressed in neoplasm tissues

To determine whether NLRs are differentially expressed in neoplasm tissues, we explored the expression of 22 NLR genes in 33 neoplasm tissues. The four most significant changed neoplasm tissues of different NLRs were shown in Fig. 1. The threshold of significant changes in mRNA levels was set at >2 or < 1/2 fold difference compared with control. As shown in the figure, NLRPs were expressed in many neoplasm tissues. For example, NLRP2 was expressed more highly in cervical squamous cell

Discussion

Within the past 10 years, NLR-mediated inflammation has been linked to the tumor-related behavior, such as tumor initiation, progression, metastasis, and survival, even alterations in the anti-tumor adaptive immune response [16]. In this study, we found different types of NLRs were differentially expressed in different tumor tissues. For example, NLRP2–3, NLRP5, NLRP7–10, and NOD2 were highly expressed in cancer tissue, and NLRP14 and NLRC4 behaved in the opposite way; while NLRP1, NOD1, NLRC3,

Declarations of interest

None.

Acknowledgments

This research was funded by the National Key R&D Program (2016YFD0501009), the Natural Science Foundation of Jiangsu Province (BK20161452), the Fundamental Research Funds for the Central Universities (KYZ201848), NJAU International Cooperation and Cultivation Project (2018-AF-20) and Graduate student scientific research innovation projects of Jiangsu Province (KYCX18_0710).

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