ABSTRACT
Nonylphenol (NP) is a widely used chemical, which has been considered a kind of endocrine-disrupting chemical and is involved in the occurrence and development of many types of cancers. Our recent studies demonstrated that NP exposure is related to colorectal cancer (CRC) progression. In this study, we also found epithelial-mesenchymal transition (EMT) promoted by NP treatment in CRC cells. However, the mechanism of NP on tumor metastasis is still unclear. In this study, we focused on the effect of the regulator of cell cycle (RGCC) induced by NP treatment. The cancer genome atlas (TCGA) analysis suggested that the expression of RGCC increased in CRC tissues, and our clinical samples showed that the expression of RGCC in tumor tissues is positively correlated with the serum level of NP in CRC patients. Further studies revealed that overexpression of RGCC could enhance the NP-induced EMT process in CRC cells and activate ERK signaling pathways. Inhibiting ERK signaling by ERK inhibitors or the knockdown of RGCC could attenuate the NP-induced EMT process. In addition, both RGCC overexpression and NP treatment could activate ERK pathways and attenuate the effect of ERK inhibitors on the EMT process in CRC cells. Altogether, this study demonstrated that NP could induce cell invasion and migration by increasing the expression of RGCC to enhance the EMT process, which might be through the activation of ERK signaling pathways. This finding supported a potential target for studying NP exposure-related colorectal cancers.
Subject(s)
Colorectal Neoplasms , Epithelial-Mesenchymal Transition , Cell Cycle , Cell Line, Tumor , Cell Movement , Cell Proliferation/genetics , Colorectal Neoplasms/metabolism , Gene Expression Regulation, Neoplastic , Humans , Phenols/pharmacologyABSTRACT
Recently, the effect of endocrine-disrupting chemicals on the cancer procession has been a concern. Nonylphenol (NP) is a common environmental estrogen that has been shown to enhance the proliferation of colorectal cancer (CRC) cells in our previous studies; however, the underlying mechanism remains unclear. In this study, we confirmed the increased concentration of NP in the serum of patients with CRC. RNA sequencing was used to explore the differentially expressed genes after NP exposure. We found 16 upregulated genes and 12 downregulated genes in COLO205 cells after NP treatment. Among these differentially expressed genes, we found that coiled-coil domain containing 80 (CCDC80) was downregulated by NP treatment and was associated with CRC progression. Further experiments revealed that the overexpression of CCDC80 significantly suppressed NP-induced cell proliferation and recovered the reduced cell apoptosis. Meanwhile, the overexpression of CCDC80 significantly inhibited the activation of ERK1/2 induced by NP treatment. ERK1/2 inhibitor (PD98059) treatment also suppressed NP-induced CRC cell growth, but the overexpression of CCDC80 did not enhance the effect of ERK1/2 inhibitor. Taken together, NP treatment significantly inhibited the expression of CCDC80, and the overexpression of CCDC80 suppressed NP-induced CRC cell growth by inhibiting the activation of ERK1/2. These results suggest that NP could induce CRC cell growth by influencing the expression of multiple genes. CCDC80 and ERK1/2 inhibitors may be suitable therapeutic targets in NP-related CRC progression.
ABSTRACT
Colorectal cancer (CRC) is the third most common cancer in the USA. MicroRNAs play important roles in the pathogenesis of CRC. In this study, we investigated the role of miR-30b in CRC and found that its expression was significantly lower in CRC tissues than that in normal tissues. We showed that a low expression level of miR-30b was closely related to poor differentiation, advanced TNM stage and poor prognosis of CRC. Further experiments showed that over-expression of miR-30b suppressed CRC cell proliferation in vitro and tumour growth in vivo. Specifically, miR-30b promoted G1 arrest and induced apoptosis. Moreover, KRAS, PIK3CD and BCL2 were identified as direct and functional targets of miR-30b. MiR-30b directly targeted the 3'-untranslated regions of their mRNAs and repressed their expression. This study revealed functional and mechanistic links between miRNA-30b and oncogene KRAS, PIK3CD and BCL2 in the pathogenesis of CRC. MiR-30b not only plays important roles in the regulation of cell proliferation and tumour growth in CRC, but is also a potential prognostic marker or therapeutic target for CRC. Restoration of miR-30b expression may represent a promising therapeutic approach for targeting malignant CRC.
Subject(s)
Colorectal Neoplasms/metabolism , Genes, Tumor Suppressor , MicroRNAs/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Proto-Oncogene Proteins/metabolism , ras Proteins/metabolism , 3' Untranslated Regions , Animals , Apoptosis , Binding Sites , Cell Differentiation , Cell Proliferation , Class I Phosphatidylinositol 3-Kinases , Colorectal Neoplasms/genetics , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , Computational Biology , Female , G1 Phase Cell Cycle Checkpoints , Gene Expression Regulation, Neoplastic , HCT116 Cells , Humans , Kaplan-Meier Estimate , Male , Mice, Inbred BALB C , Mice, Nude , MicroRNAs/genetics , Middle Aged , Neoplasm Staging , Phosphatidylinositol 3-Kinases/genetics , Prognosis , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins p21(ras) , RNA, Messenger/metabolism , Signal Transduction , Time Factors , Transfection , Tumor Burden , ras Proteins/geneticsABSTRACT
BACKGROUND: T lymphoma invasion and metastasis 1 (Tiam1) is a potential modifier of tumor development and progression. Our previous study in vitro and in nude mice suggested a promotion role of Tiam1 on invasion and metastasis of colorectal cancer (CRC). In the present study, we generated Tiam1/C1199-CopGFP transgenic mice to investigate the tumorigenetic, invasive and metastatic alterations in the colon and rectum of wild-type and Tiam1 transgenic mice under 1,2-dimethylhydrazine (DMH) treatment. METHODS: Transgenic mice were produced by the method of pronuclear microinlectlon. Whole-body fluorescence imaging (Lighttools, Edmonton, Alberta, Canada), PCR, and immunohistochemical techniques (IHC) were applied sequentially to identify the transgenic mice. The carcinogen DMH (20 mg/kg) was used to induce colorectal tumors though intraperitoneal (i.p.) injections once a week for 24 weeks from the age of 4 weeks on Tiam1 transgenic or non-transgenic mice. RESULTS: We successfully generated Tiam1/C1199-CopGFP transgenic mice and induced primary tumors in the intestine of both wild type and Tiam1 transgenic mice by DMH treatment. In addition, Tiam1 transgenic mice developed larger and more aggressive neoplasm than wild-type mice. Moreover, immunohistochemical staining revealed that upregulation of Tiam1 was correlated with increased expression of ß-Catenin and Vimentin, and downregulation of E-Cadherin in these mice. CONCLUSIONS: Our study has provided in vivo evidence supporting that Tiam1 promotes invasion and metastasis of CRC, most probably through activation of Wnt/ß-catenin signaling pathway, in a Tiam1 transgenic mouse model.
