Dataset Information

Cyclovirobuxine D inhibits colorectal cancer tumorigenesis via the CTHRC1?AKT/ERK?Snail signaling pathway.

ABSTRACT: Cyclovirobuxine D (CVB?D) is an alkaloid, which is mainly derived from Buxus microphylla. It has been reported that CVB?D has positive effects on breast cancer, gastric cancer and other malignant tumors. However, to the best of our knowledge, there are no reports regarding the effects of CVB?D on colorectal cancer (CRC). The purpose of the present study was to determine the anticancer effects of CVB?D and further elucidate its molecular mechanism(s). DLD?1 and LoVo cell lines were selected to evaluate the antitumor effect of CVB?D. Cytotoxicity, viability and proliferation were evaluated by the MTT and colony formation assays. Flow cytometry was used to detect the effects on apoptosis and the cell cycle in CVB?D?treated CRC cells. The migration and invasion abilities of CRC cells were examined by wound healing and Transwell assays. In addition, RNA sequencing, bioinformatics analysis and western blotting were performed to investigate the target of drug action and clarify the molecular mechanisms. A xenograft model was established using nude mice, and ultrasound was employed to assess the preclinical therapeutic effects of CVB?D in vivo. It was identified that CVB?D inhibited the proliferation, migration, stemness, angiogenesis and epithelial?mesenchymal transition of CRC cells, and induced apoptosis and S?phase arrest. In addition, CVB?D significantly inhibited the growth of xenografts. It is notable that CVB?D exerted anticancer effects in CRC cells partly by targeting collagen triple helix repeat containing 1 (CTHRC1), which may be upstream of the AKT and ERK pathways. CVB?D exerted anticancer effects through the CTHRC1?AKT/ERK?Snail signaling pathway. Targeted therapy combining CTHRC1 with CVB?D may offer a promising novel therapeutic approach for CRC treatment.

SUBMITTER: Jiang F

PROVIDER: S-EPMC7252468 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Cyclovirobuxine D inhibits colorectal cancer tumorigenesis via the CTHRC1‑AKT/ERK‑Snail signaling pathway.

Jiang Fengqi F Chen Yaodong Y Ren Shuo S Li Zizhuo Z Sun Kan K Xing Yanwei Y Zhu Yuekun Y Piao Daxun D

International journal of oncology 20200403 1

Cyclovirobuxine D (CVB‑D) is an alkaloid, which is mainly derived from Buxus microphylla. It has been reported that CVB‑D has positive effects on breast cancer, gastric cancer and other malignant tumors. However, to the best of our knowledge, there are no reports regarding the effects of CVB‑D on colorectal cancer (CRC). The purpose of the present study was to determine the anticancer effects of CVB‑D and further elucidate its molecular mechanism(s). DLD‑1 and LoVo cell lines were selected to ev ...[more]

PMID: 32319595

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Project description:Background Histone epigenetic modification disorder is an important predisposing factor for the occurrence and development of many cancers, including colorectal cancer (CRC). The role of MYSM1, a metalloprotease that deubiquitinates monoubiquitinated histone H2A, in colorectal cancer was identified to evaluate its potential clinical application value. Methods MYSM1 expression levels in CRC cell lines and tumor tissues were detected, and their associations with patient survival rate and clinical stage were analyzed using databases and tissue microarrays. Gain- and loss-of-function studies were performed to identify the roles of MYSM1 in CRC cell proliferation, apoptosis, cell cycle progression, epithelial-mesenchymal transition (EMT) and metastasis in vitro and in vivo. ChIP, rescue assays and signal pathway verification were conducted for mechanistic study. Immunohistochemistry (IHC) was used to further assess the relationship of MYSM1 with CRC diagnosis and prognosis. Results MYSM1 was significantly downregulated and was related to the overall survival (OS) of CRC patients. MYSM1 served as a CRC suppressor by inducing apoptosis and inhibiting cell proliferation, EMT, tumorigenic potential and metastasis. Mechanistically, MYSM1 directly bound to the promoter region of miR-200/CDH1, impaired the enrichment of repressive H2AK119ub1 modification and epigenetically enhanced miR-200/CDH1 expression. Testing of paired CRC patient samples confirmed the positive regulatory relationship between MYSM1 and miR-200/CDH1. Furthermore, silencing MYSM1 stimulated PI3K/AKT signaling and promoted EMT in CRC cells. More importantly, a positive association existed between MYSM1 expression and a favorable CRC prognosis. Conclusions MYSM1 plays essential suppressive roles in CRC tumorigenesis and is a potential target for reducing CRC progression and distant metastasis. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-02106-2.

Project description:BackgroundColon cancer (CC) ranks the second highest mortality rate among malignant tumors worldwide, and the current mainstream treatment regimens are not very effective. The unique efficacy of Chinese herb medicine (CHM) for cancer has recently attracted increasing attention. Cinnamomi Ramulus (CR), as a classic CHM, has been widely used in the treatment of a variety of diseases for hundreds of years in China, but its specific pharmacological mechanism against CC needs to be fully evaluated.MethodsTCMSP and China National Knowledge Infrastructure database were utilized to predict the candidate ingredients of CR, and TCMSP and SwissTargetPrediction database were also employed to predict the drug targets of the candidate ingredients from CR. We subsequently evaluated the therapeutic effect of CR by orally administrating it on CC-bearing mice. Next, we further identified the potential CC-related targets by using Gene Expression Omnibus (GEO) database. Based on these obtained targets, the drug/disease-target PPI networks were constructed using Bisogenet plugin of Cytoscape. The potential core therapeutic targets were then identified through topological analysis using CytoNCA plugin. GO and KEGG enrichment analyses were performed to predict the underlying mechanism of CR against CC. Furthermore, these in silico analysis results were validated by a series of cellular functional and molecular biological assays. UPLC-MS/MS method and molecular docking analysis were employed to identify the potential key components from CR.ResultsIn this study, we firstly found that CR has potential therapeutic effect on cancer. Then, oral administration of CR could inhibit the growth of CC cells in C57BL/6 mice, while inhibiting the viability and motility of CC cells in vitro. We obtained 111 putative core therapeutic targets of CR. Subsequent enrichment analysis on these targets showed that CR could induce apoptosis and cell cycle arrest in CC cells by blocking Akt/ERK signaling pathways, which was further experimentally verified. We identified 5 key components from the crude extract of CR, among which taxifolin was found most likely to be the key active component against CC.ConclusionsOur results show that CR as well as its active component taxifolin holds great potential in treatment of CC.

Dataset Information

Cyclovirobuxine D inhibits colorectal cancer tumorigenesis via the CTHRC1?AKT/ERK?Snail signaling pathway.

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Cyclovirobuxine D inhibits colorectal cancer tumorigenesis via the CTHRC1‑AKT/ERK‑Snail signaling pathway.

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