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FBW7 suppresses metastasis of colorectal cancer by inhibiting HIF1?/CEACAM5 functional axis.

ABSTRACT: F-box and WD repeat domain-containing 7 (FBW7) functions as a major tumor suppressor by targeting oncoproteins for degradations. FBW7 has been reported to be one of the most frequently mutated genes in colorectal cancer (CRC). However, its roles and possible mechanisms in the development of CRC are still unclear. In the present study, we adopted immunohistochemistry staining in tissue microarray (TMA), consisting of 276 samples from stage I-IV CRC patients, and analyzed the correlation between FBW7 expression and clinicopathological parameters, as well as overall survival (OS) and disease-free survival (DFS). The impact of FBW7 on migration was further validated in vitro. Whole-genome expression microarray (GEO,accession numbers GSE76443), was then analyzed to find the possible target of FBW7. The results were verified by functional experiments in vitro and IHC staining of TMA. Finally, luciferase and chromatin immunoprecipitation (ChIP) assays were carried out to identify the possible mechanisms. The expression level of FBW7 in TMA was negatively correlated with serum CEA level, venous invasion, N stage and M stage, and positively associated with the survival of CRC patients(P<0.05). Ectopic FBW7 expression significantly suppressed migration of colon cancer cells in vitro. GEO analysis revealed that decreased FBW7 significantly correlated with increased level of CEACAM5, which encoded CEA. The correlation was verified by IHC of TMA and silencing CEACAM5 inhibited migration in vitro. Mechanistically, we demonstrated that CEACAM5 was a HIF1? target gene and that FBW7 regulated CEACAM5 in a HIF1?-dependent manner. In conclusion, our results revealed that FBW7 suppressed migration through regulation of the HIF1?/CEACAM5 axis in colorectal cancer. Therefore, our study sheds novel lights on the impact of FBW7 on HIF1?/CEACAM5 signaling axis and constitutes potential prognostic predictors and therapeutic targets for CRC.

SUBMITTER: Li Q

PROVIDER: S-EPMC6001674 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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FBW7 suppresses metastasis of colorectal cancer by inhibiting HIF1α/CEACAM5 functional axis.

Li Qingguo Q Li Yaqi Y Li Jing J Ma Yanlei Y Dai Weixing W Mo Shaobo S Xu Ye Y Li Xinxiang X Cai Sanjun S

International journal of biological sciences 20180512 7

F-box and WD repeat domain-containing 7 (FBW7) functions as a major tumor suppressor by targeting oncoproteins for degradations. FBW7 has been reported to be one of the most frequently mutated genes in colorectal cancer (CRC). However, its roles and possible mechanisms in the development of CRC are still unclear. In the present study, we adopted immunohistochemistry staining in tissue microarray (TMA), consisting of 276 samples from stage I-IV CRC patients, and analyzed the correlation between F ...[more]

PMID: 29910683

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Project description:BACKGROUND:Klotho (KL) was originally characterized as an aging suppressor gene, and has been identified as a tumor suppressor gene in a variety of cancers, including colorectal cancer. Recent years have witnessed the importance of metabolism transformation in cancer cell malignancies maintenance. Aberrant cancer cell metabolism is considered to be the hallmark of cancer. Our previous studies demonstrated that KL played negative roles in colon cancer cell proliferation and metastasis. However, its role in the cancer cell reprogramming has seldom been reported. The aim of this study was to examine the role of KL in aerobic glycolysis in colorectal cancer. METHODS:Combining maximum standardized uptake value (SUVmax), which was obtained preoperatively via a PET/CT scan, with immunohistochemistry staining, we analyzed the correlation between SUVmax and KL expression in colorectal cancer tissues. The impact of KL on glucose metabolism and its mechanisms were further validated in vitro and in vivo. RESULTS:Patients with lower KL expression exhibited higher 18F-FDG uptake (P?<?0.05), indicating that KL might participate in aerobic glycolysis regulation. In vitro assay by using colon cancer cell lines further supported this observation. By overexpressing KL in HTC116 and SW480 cells, we observed that the glycolysis was inhibited and the mitochondrial respiration increased, indicating that KL was a negative regulator of aerobic glycolysis. To seek for the underlying mechanisms, we tried to dig out the relation between KL and HIF1? signaling pathway, and found that KL negatively regulated HIF1? protein level and transcriptional activity. Western blot analysis showed that KL overexpression negatively regulated ERK pathway, and KL regulated aerobic glycolysis in part through its regulation of ERK/ HIF1? axis. CONCLUSIONS:Taken together, KL is a negative regulator of aerobic glycolysis and KL inhibited glucose metabolism transformation via the ERK/ HIF1? axis.

Project description:BackgroundThe investigation of underlying mechanism and the exploitation of novel therapies for metastatic prostate cancer (PCa) are still urgently needed. miR-199b-5p has been suggested to function as tumour suppressor in various human cancers. However, the clinical significance and role of miR-199b-5p in PCa remain unclear.MethodsThe current study sought to investigate the expression status of miR-199b-5p in PCa and the involved molecular mechanisms in PCa metastasis by using bioinformatics analyses, loss-and gain-of-functions and rescue experiments in vitro and in vivo.ResultsWe demonstrated that miR-199b-5p was significantly downregulated in metastatic PCa tissues and cells when compared with the normal prostate tissue, the localised disease, the weakly metastatic and androgen-dependent PCa cell and the normal prostate epithelial cell. We also found that miR-199b-5p drastically suppressed PCa cell proliferation, migration and invasion in vitro and inhibited xenografts tumour growth and metastasis in vivo. Mechanistically, our results showed that miR-199b-5p could inhibit discoidin domain receptor tyrosine kinase 1 (DDR1) expression by directly targeting its 3'-UTR, thereby hindering epithelial-mesenchymal transition (EMT)-associated traits, which were induced by DDR1 activating ERK signalling pathway. Moreover, PCa patients with low miR-199b-5p expression level had a remarkably shorter overall survival than those with high miR-199b-5p level, indicating an association of miR-199b-5p loss with poor prognosis in patients with PCa. Furthermore, DDR1 was upregulated in PCa, and significantly correlated with high Gleason score, advanced pathological stage, tumour metastasis and shorter overall survival.ConclusionsOur study, for the first time, provide evidence of a tumour-suppressive function of miR-199b-5p in the invasion and metastasis of PCa, supporting the translational exploitation of miR-199b-5p-based therapeutic approaches for PCa metastases. Also, the miR-199b-5p-DDR1-ERK signalling axis identified in this study represents a novel mechanism of regulating EMT in PCa metastases.

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FBW7 suppresses metastasis of colorectal cancer by inhibiting HIF1?/CEACAM5 functional axis.

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FBW7 suppresses metastasis of colorectal cancer by inhibiting HIF1α/CEACAM5 functional axis.

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