Keratin 8 limits TLR-triggered inflammatory responses through inhibiting TRAF6 polyubiquitination

Dong, Xiaofang; Liu, En Dong; Meng, Yun; Liu, Chao; Bi, Ya Lan; Wu, Huanwen; Jin, Yan; Yao, Jing; Tang, Liu Jun; Wang, Jian; Li, Min; Zhang, Chao; Yu, Miao; Zhan, Yi Qun; Chen, Hui; Ge, Chang; Yang, Xiao Ming; Li, Chang Yan

doi:10.1038/srep32710

Cited by 15 publications

(13 citation statements)

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“…19 KRT8 plays important roles not only in maintaining cellular structural integrity, but also in various pathological progress, such as insulin resistance, 20 retinal pigment epithelium degeneration, 21 inflammatory responses. 22 Notably, recent studies showed that KRT8 is also involved in tumor progress. KRT8 up-regulation promoted renal cell carcinoma metastasis via IL-11/STAT3 pathway, 23 enhanced migration of gastric cancer cells through TGF-β pathway.…”

Section: Discussionmentioning

confidence: 99%

<p>The Metastasis Potential Promoting Capacity of Cancer-Associated Fibroblasts Was Attenuated by Cisplatin via Modulating KRT8</p>

Song¹,

Guo²,

Wang³

et al. 2020

OTT

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Background: Cancer-associated fibroblasts (CAFs) are an essential component of tumor microenvironment. They are attracting increasing attentions due to their crucial role in tumor growth, drug-resistance and metastasis. Cisplatin is a first-line chemotherapy drug applying in various types of cancer. There are intensive studies on cisplatin's effect on tumor cells, however, its effect on CAFs remains poorly understood. In the present study, we investigated the effect of cisplatin on CAFs. Methods: Cell migration was detected by wound healing assay. Cell invasion was performed by the transwell assay. mRNA expression was detected by quantitative PCR, and protein expression was detected by Western blotting. Tumor growth was measured using BALB/c nude mice tumor models. Results: Cisplatin attenuated the promoting capacity of CAFs on lung cancer cell migration and invasion, via suppressing CAFs' effect on metastasis-related genes including Twist1, vascular endothelial growth factor receptor (VEGFR), MMP2, and AKT signaling pathway. Keratin 8 (KRT8) was identified as a target of cisplatin. KRT8 upregulation in CAFs is responsible for the inhibitory effect of cisplatin on lung cancer cells metastasis potential through AKT pathway suppression. The stimulation of AKT by AKT activator SC79 reversed KRT8's effect on cell migration. Importantly, in vivo study also showed that CAFs enhanced tumor growth significantly, and cisplatin effectively abrogated the promoting effect of CAFs on tumor growth. Conclusion: Our results revealed a novel mechanism that cisplatin attenuated the metastasis promoting effect of CAFs via KRT8/AKT signaling pathway. This finding highlights KRT8 in CAFs as a potential therapeutic candidate for metastasis treatment.

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Section: Discussionmentioning

confidence: 99%

<p>The Metastasis Potential Promoting Capacity of Cancer-Associated Fibroblasts Was Attenuated by Cisplatin via Modulating KRT8</p>

Song¹,

Guo²,

Wang³

et al. 2020

OTT

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“…There is increasing evidence that CK8 may be an important signaling molecule regulating the inflammatory response. Our previous study indicated that CK8 prevented the polyubiquitination of TRAF6, thus suppressing NF-κB signaling and TLR-dependent inflammation [ 14 ]. In addition, chronic colitis was found to occur spontaneously in homozygous CK8 −/− FVB/N mice [ 9 ].…”

Section: Discussionmentioning

confidence: 99%

“…Embryonic lethality has been reported to occur in about 50% of homozygous CK8 knockout mice. Our previous study demonstrated that CK8 was completely abolished in CK8 −/− mice, while CK8 +/− mice had about half the CK8 level of CK8 +/+ mice in all examined tissues [ 14 ]. Furthermore, CK8 +/− mice were phenotypically similar to wild-type (WT) controls, with only slight crypt proliferation and partial ion transport dysfunction [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Keratin 8 reduces colonic permeability and maintains gut microbiota homeostasis, protecting against colitis and colitis-associated tumorigenesis

Liu

Meng

et al. 2017

Oncotarget

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Keratin 8 (CK8) is the major component of the intermediate filaments of simple or single-layered epithelia. Gene targeting mice model suggest that CK8 is involved in colonic active ion transport, colorectal hyperplasia and inflammation. In the present study, we found that CK8 is downregulated in the colon during DSS-induced colitis and AOM/DSS-induced colitis-associated colorectal cancer (CAC) development. In human patients with colon cancer, CK8 is downregulated. Using CK8 heterozygous knockout mice (CK8+/−), we found that CK8+/− mice are highly susceptible to DSS-induced colitis and more prone to AOM/DSS-induced CAC than wild type (WT) mice. The colonic permeability is increased with DSS or AOM/DSS treatment, leading to alteration of gut microbiota in CK8+/− mice with CAC. Metagenomic analysis of fecal microbiota suggests Firmicutes and Proteobacteria are increased in CK8+/− mice with CAC, while Bacteroidetes and Verrucomicrobia are decreased. Antibiotic treatment decreases the incidence of colorectal cancer tumorigenesis and TLR4 inhibitor attenuates the susceptibility of CK8+/− mice to DSS-induced colitis. These data suggest CK8 protects mice from colitis and colitis-associated colorectal cancer by modulating colonic permeability and gut microbiota composition homeostasis.

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“…In a recent study, K8 was suggested to be a negative regulator of TLR‐mediated signalling, as it was shown that K8 downregulation in mice leads to increased TLR responses, higher inflammatory cytokine levels and more inflammatory tissue injury in response to lipopolysaccharide‐induced sepsis 31. It is possible that the aggravated diabetes in K8 +/− mice in the present study also, in part, may stem from upregulated inflammatory responses due to increased TLR signalling in the K8‐compromised mice, and this potential association warrants further study.…”

Section: Discussionmentioning

confidence: 99%

Decreased levels of keratin 8 sensitize mice to streptozotocin‐induced diabetes

et al. 2018

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AimDiabetes is a result of an interplay between genetic, environmental and lifestyle factors. Keratin intermediate filaments are stress proteins in epithelial cells, and keratin mutations predispose to several human diseases. However, the involvement of keratins in diabetes is not well known. K8 and its partner K18 are the main β‐cell keratins, and knockout of K8 (K8−/−) in mice causes mislocalization of glucose transporter 2, mitochondrial defects, reduced insulin content and altered systemic glucose/insulin control. We hypothesize that K8/K18 offer protection during β‐cell stress and that decreased K8 levels contribute to diabetes susceptibility.MethodsK8‐heterozygous knockout (K8+/−) and wild‐type (K8+/+) mice were used to evaluate the influence of keratin levels on endocrine pancreatic function and diabetes development under basal conditions and after T1D streptozotocin (STZ)‐induced β‐cell stress and T2D high‐fat diet (HFD).ResultsMurine K8+/− endocrine islets express ~50% less K8/K18 compared with K8+/+. The decreased keratin levels have little impact on basal systemic glucose/insulin regulation, β‐cell health or insulin levels. Diabetes incidence and blood glucose levels are significantly higher in K8+/− mice after low‐dose/chronic STZ treatment, and STZ causes more β‐cell damage and polyuria in K8+/− compared with K8+/+. K8 appears upregulated 5 weeks after STZ treatment in K8+/+ islets but not in K8+/−. K8+/− mice showed no major susceptibility risk to HFD compared to K8+/+.ConclusionPartial K8 deficiency reduces β‐cell stress tolerance and aggravates diabetes development in response to STZ, while there is no major susceptibility to HFD.

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Keratin 8 limits TLR-triggered inflammatory responses through inhibiting TRAF6 polyubiquitination

Cited by 15 publications

References 50 publications

<p>The Metastasis Potential Promoting Capacity of Cancer-Associated Fibroblasts Was Attenuated by Cisplatin via Modulating KRT8</p>

<p>The Metastasis Potential Promoting Capacity of Cancer-Associated Fibroblasts Was Attenuated by Cisplatin via Modulating KRT8</p>

Keratin 8 reduces colonic permeability and maintains gut microbiota homeostasis, protecting against colitis and colitis-associated tumorigenesis

Decreased levels of keratin 8 sensitize mice to streptozotocin‐induced diabetes

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