Emerging role of F-box proteins in the regulation of epithelial-mesenchymal transition and stem cells in human cancers

Song, Yizuo; Lin, Min; Liu, Yi; Wang, Zhiwei; Zhu, Xueqiong

doi:10.1186/s13287-019-1222-0

Cited by 31 publications

(23 citation statements)

References 149 publications

(172 reference statements)

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“…We found that FBXL8 blocks apoptosis of BRCA cells and modulates cytokine profiles to promote a pro-inflammatory condition. Furthermore, we showed that knockdown of FBXL8 induced intrinsic apoptosis of the BRCA cells, suggesting that FBXL8 promotes BRCA advancement, as supported by the involvement of other F-box proteins in regulating the EMT process in cancers [14]. Consistently, we demonstrated that the loss of FBXL8 decreased cell migration and invasion, affirming that FBXL8 is a key promoter of BRCA progression and metastasis.…”

Section: Discussionsupporting

confidence: 74%

“…To test this hypothesis, we first identified the specific SCF E3 ligases and their potential pathobiological partners, and then explore their mechanisms in driving BRCA progression, with a view to understanding how the SCF E3 ubiquitin ligases might act as significant risk factors in cancer advancement [ 13 ]. Since the F-box is responsible for the functional specificity of SCF E3 tetrameric complex [ 14 ], we focused our attention on the expression profiles of F-box factors. Notably, there are 71 genes in the human “F-box gene family”, including: (1) 21 F-boxes grouped as leucine-rich repeat protein, (2) 11 F-boxes with WD repeat domain and (3) 39 F-boxes grouped as “others” [ 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

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Human FBXL8 Is a Novel E3 Ligase Which Promotes BRCA Metastasis by Stimulating Pro-Tumorigenic Cytokines and Inhibiting Tumor Suppressors

Chang

Hsu

et al. 2020

Cancers

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The initiation and progression of breast cancer (BRCA) is associated with inflammation and immune-overactivation, which is critically modulated by the E3 ubiquitin ligase. However, the underlying mechanisms and key factors involved in BRCA formation and disease advancement remains under-explored. By retrospective studies of BRCA patient tissues; and gene knockdown and gain/loss-of-function studies, we uncovered a novel E3 ligase, FBXL8, in BRCA. A signature expression profile of F-box factors that specifically target and degrade proteins involved in cell death/survival, was identified. FBXL8 emerged as a prominent member of the F-box factors. Ex vivo analysis of 1349 matched BRCA tissues indicated that FBXL8 promotes cell survival and tumorigenesis, and its level escalates with BRCA progression. Knockdown of FBXL8 caused: (i) intrinsic apoptosis, (ii) inhibition of cell migration and invasion, (iii) accumulation of two tumor-suppressors, CCND2 and IRF5, and (iv) downregulation of cancer-promoting cytokines/chemokines; all of which curtailed the tumor microenvironment and displayed potential to suppress cancer progression. Co-IP study suggests that two tumor-suppressors, CCND2 and IRF5 are part of the immune-complex of FBXL8. The protein levels of CCND2 and IRF5 inversely correlated with FBXL8 expression, implying that FBXL8 E3 ligase was associated with the degradation of CCND2 and IRF5. Altogether, we propose the exploitation of the ubiquitin signaling axis of FBXL8-CCND2-IRF5 for anti-cancer strategies and potential therapeutics.

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Section: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Human FBXL8 Is a Novel E3 Ligase Which Promotes BRCA Metastasis by Stimulating Pro-Tumorigenic Cytokines and Inhibiting Tumor Suppressors

Chang

Hsu

et al. 2020

Cancers

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“…Its special relevance is also highlighted by the fact that it appears to reveal co-occurrence with two mutations, specifically RB1 and PIK3CA, which were also detected in the presented cases. Other genes related to neuroendocrine differentiation, like ASCL1, may also play a role in the development of the neuroendocrine component, especially since ASCL1 is involved in the Notch-Hes1 axis, which is analogous to the Wnt-beta catenin signalling pathway, altered by the FBXW7 mutation [51][52][53]. Our findings may expedite the understanding of combined tumour development in the colon and in addition help establish awareness for such rare neoplasms, although continuing research, especially with regard to divergent differentiation of neuroendocrine-and squamous-related genes, is necessary to fully decode the development of this combined neoplasm.…”

Section: Woischke Et Almentioning

confidence: 99%

Mixed large cell neuroendocrine carcinoma and squamous cell carcinoma of the colon: detailed molecular characterisation of two cases indicates a distinct colorectal cancer entity

Woischke

Jung

Kumbrink

et al. 2020

The Journal of Pathology CR

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We present two rare cases of mixed large cell neuroendocrine carcinoma and squamous cell carcinoma of the colon. A literature search revealed only three published cases with similar histology but none of these reports provided profound molecular and mutational analyses. Our two cases exhibited a distinct, colon-like immunophenotype with strong nuclear CDX2 and β-catenin expression in more than 90% of the tumour cells of both components. We analysed the two carcinomas regarding microsatellite stability, RAS, BRAF and PD-L1 status. In addition, next-generation panel sequencing with Ion AmpliSeq™ Cancer Hotspot Panel v2 was performed. This approach revealed mutations in FBXW7, CTNNB1 and PIK3CA in the first case and FBXW7 and RB1 mutations in the second case. We looked for similar mutational patterns in three publicly available colorectal adenocarcinoma data sets, as well as in collections of colorectal mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) and colorectal neuroendocrine carcinomas. This approach indicated that the FBXW7 point mutation, without being accompanied by classical adenoma-carcinoma sequence mutations, such as APC, KRAS and TP53, likely occurs at a relatively high frequency in mixed neuroendocrine and squamous cell carcinoma and therefore may be characteristic for this rare tumour type. FBXW7 codifies the substrate recognition element of an ubiquitin ligase, and inactivating FBXW7 mutations lead to an exceptional accumulation of its target β-catenin which results in overactivation of the Wnt-signalling pathway. In line with previously described hypotheses of dedifferentiation of colon cells by enhanced Wnt-signalling, our data indicate a crucial role for mutant FBXW7 in the unusual morphological switch that determines these rare neoplasms. Therefore, mixed large cell neuroendocrine and a squamous cell carcinoma can be considered as a distinct carcinoma entity in the colon, defined by morphology, immunophenotype and distinct molecular genetic alteration(s).

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“…F-box proteins have been validated to play a pivotal role in carcinogenesis and progression 13,15 . They are involved in various physiological and pathological processes which include proliferation, apoptosis, metastasis, cancer stem cell generation, epithelial-mesenchymal transition (EMT), drug resistance in human cancers [16][17][18] . It is important to notice that F-box proteins, including FBXO22, have oncogenic or tumor suppressive role in cancer development and progression.…”

Section: Introductionmentioning

confidence: 99%

Emerging role of FBXO22 in carcinogenesis

et al. 2020

Self Cite

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The F-box protein 22 (FBXO22), one of F-box proteins, has been identified to be critically involved in carcinogenesis. FBXO22 promotes proliferation in breast cancer and lung cancer, but suppresses migration and metastasis. FBXO22 exerts oncogenetic functions via promoting the ubiquitination and degradation of its substrates, including KDM4A, KDM4B, methylated p53, p21, KLF4, LKB1, Snail, CD147, Bach1, PTEN, and HDM2. FBXO22 is also regulated by several regulatory factors such as p53, miR-155, SNHG14, and circ_0006282. In this review, we summarize the regulatory factors and downstream targets of FBXO22 in cancers, discuss its functions in tumorigenesis, and further highlight the alteration of FBXO22 expression in a variety of human malignancies. Finally, we provide novel insights for future perspectives on targeting FBXO22 as a promising strategy for cancer therapy. Facts FBXO22 targets multiple substrates for ubiquitination and degradation. FBXO22 is critically involved in tumorigenesis and tumor progression. FBXO22 might be a therapeutic target for cancer treatment. Open questions Which targets of FBXO22 are pivotal for cancer development and malignant progression? Do E3 liagses regulate the protein levels of FBXO22? How the inhibitors of FBXO22 could be developed and discovered for cancer therapy?

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Emerging role of F-box proteins in the regulation of epithelial-mesenchymal transition and stem cells in human cancers

Cited by 31 publications

References 149 publications

Human FBXL8 Is a Novel E3 Ligase Which Promotes BRCA Metastasis by Stimulating Pro-Tumorigenic Cytokines and Inhibiting Tumor Suppressors

Human FBXL8 Is a Novel E3 Ligase Which Promotes BRCA Metastasis by Stimulating Pro-Tumorigenic Cytokines and Inhibiting Tumor Suppressors

Mixed large cell neuroendocrine carcinoma and squamous cell carcinoma of the colon: detailed molecular characterisation of two cases indicates a distinct colorectal cancer entity

Emerging role of FBXO22 in carcinogenesis

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