Depletion of keratin 8/18 modulates oncogenic potential by governing multiple signaling pathways

Tiwari, Richa; Sahu, Indrajit; Soni, Bihari Lal; Sathe, Gajanan; Thapa, Pankaj; Patel, Pavan; Sinha, Shruti; Vadivel, Chella Krishna; Patel, Shweta; Jamghare, Sayli; Oak, Swapnil; Thorat, Rahul; Gowda, Harsha; Vaidya, Milind M.

doi:10.1111/febs.14401

Cited by 13 publications

(10 citation statements)

References 87 publications

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“…Interestingly in skin epidermis during the hair follicle cycle, K17 modulates TNFα signaling and NFκB activity through its interaction with an adaptor protein TRADD to suppress apoptosis (Figure 2A) [91], thus, a similar mechanism may take place in cancer settings. Similarly, downregulation of K8 altered TMS1-NF-κB signaling cascade, leading to increased apoptosis and significantly reduced tumorigenic potential of skin squamous carcinoma cells (Figure 2A) [92]. K8 and K18 also function in the liver to help hepatocytes cope with mechanical and nonmechanical stress that can result in apoptosis and necrosis [93,94], and a recent study by Bozza et al also showed that K8 and K18 protect breast cancer cells from TRAIL-induced apoptosis by downregulating death receptor expression (Figure 2A) [95].…”

Section: Impacts Of Intermediate Filament Proteins On Cancer Hallmmentioning

confidence: 99%

Intermediate Filaments as Effectors of Cancer Development and Metastasis: A Focus on Keratins, Vimentin, and Nestin

Sharma

Alsharif

Fallatah

et al. 2019

Cells

121

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Intermediate filament (IF) proteins make up the largest family of cytoskeletal proteins in metazoans, and are traditionally known for their roles in fostering structural integrity in cells and tissues. Remarkably, individual IF genes are tightly regulated in a fashion that reflects the type of tissue, its developmental and differentiation stages, and biological context. In cancer, IF proteins serve as diagnostic markers, as tumor cells partially retain their original signature expression of IF proteins. However, there are also characteristic alterations in IF gene expression and protein regulation. The use of high throughput analytics suggests that tumor-associated alterations in IF gene expression have prognostic value. Parallel research is also showing that IF proteins directly and significantly impact several key cellular properties, including proliferation, death, migration, and invasiveness, with a demonstrated impact on the development, progression, and characteristics of various tumors. In this review, we draw from recent studies focused on three IF proteins most associated with cancer (keratins, vimentin, and nestin) to highlight how several “hallmarks of cancer” described by Hanahan and Weinberg are impacted by IF proteins. The evidence already in hand establishes that IF proteins function beyond their classical roles as markers and serve as effectors of tumorigenesis.

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Section: Impacts Of Intermediate Filament Proteins On Cancer Hallmmentioning

confidence: 99%

Intermediate Filaments as Effectors of Cancer Development and Metastasis: A Focus on Keratins, Vimentin, and Nestin

Sharma

Alsharif

Fallatah

et al. 2019

Cells

121

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“…KRT8 upregulated expression can promote the metastasis of clear cell renal cell carcinoma (ccRCC) cells by up-regulating IL-11 expression, inducing IL-11 autocrine, and initiating the STAT3 signaling pathway [15]. Loss of keratin 8/18 can regulate oncogenic potential by controlling various signaling pathways, including TMS1-NF-κB signaling and MARCKSL1-Paxillin1-Rac axis, in skin squamous cell carcinomas (SCC) [16]. The KRT8 protein can bind to annexin A2 and mediate both the apoptosis and the redox pathway in anaplastic thyroid carcinoma (ATC) [17].…”

Section: Introductionmentioning

confidence: 99%

High KRT8 Expression Independently Predicts Poor Prognosis for Lung Adenocarcinoma Patients

Xie

Dang

Guo

et al. 2019

Genes

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Keratin 8 (KRT8), a type II basic intermediate filament (IF) protein, is essential for the development and metastasis of various cancers. In this study, by analyzing RNA-seq data from the Cancer Genome Atlas (TCGA)-lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), we have determined the expression profile of KRT8, and assessed its prognostic significance and the possible mechanism underlying the dysregulation. Our results showed that KRT8 mRNA expression was significantly up-regulated in both LUAD and LUSC tissues compared with normal lung tissues. The high KRT8 expression group for LUAD patients significantly reduced overall survival (OS) and recurrence-free survival (RFS). Univariate and multivariate analysis revealed that KRT8 expression was an independent prognostic indicator for poor OS and RFS in LUAD patients. However, KRT8 expression had no prognostic value in terms of OS and RFS for LUSC. By exploring DNA copy number alterations (CNAs) of the KRT8 gene in LUAD, we found that DNA low copy gain (+1 and +2) was associated with elevated KRT8 mRNA expression. From the above findings, we have deduced that KRT8 is aberrantly expressed in LUAD tissues and that its expression might independently predict poor OS and RFS for LUAD patients, but not for LUSC patients.

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“…The MARCKS family of proteins differ in subcellular location and membrane binding affinity, and includes the myristoylated alanine-rich C-kinase substrate-like 1 (MARCKSL1), also known as MARCKS-related protein (MRP) and MARCKS-like protein (MLP) [20]. MARCKSL1 is a membrane-bound actin cytoskeleton regulator [18, 21], associated with tumorigenesis in several cancer types [22, 23]. In breast cancer cell lines, MARCKSL1 knockdown results in decreased migration [24].…”

Section: Introductionmentioning

confidence: 99%

Validation study of MARCKSL1 as a prognostic factor in lymph node-negative breast cancer patients

et al. 2019

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Protein expression of Myristoylated alanine-rich C kinase substrate like-1 (MARCKSL1) has been identified as a prognostic factor in lymph-node negative (LN-) breast cancer patients. We aim to validate MARCKSL1 protein expression as a prognostic marker for distant metastasis-free survival (DMFS) in a new cohort of LN- breast cancer patients. MARCKSL1 expression was evaluated in 151 operable T1,2N0M0 LN- breast cancer patients by immunohistochemistry. Median follow-up time was 152 months, range 11–189 months. Results were compared with classical prognosticators (age, tumor diameter, grade, estrogen receptor, and proliferation) using single (Kaplan-Meier) and multivariate (Cox model) survival analysis. Thirteen patients (9%) developed distant metastases. With both single and multiple analysis of all features, MARCKSL1 did not show a significant prognostic value for DMFS (p = 0.498). Of the assessed classical prognosticators, only tumor diameter showed prognostic value (hazard ratio 9.3, 95% confidence interval 2.8–31.0, p <0.001). MARCKSL1 expression could not be confirmed as a prognostic factor in this cohort. Possible reasons include changes in diagnostic and treatment guidelines between the discovery and validation cohorts. Further studies are needed to reveal the potential biological role of this protein in breast cancer.

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Depletion of keratin 8/18 modulates oncogenic potential by governing multiple signaling pathways

Abstract: Proteome Xchange Consortium via PRIDE database (dataset identifier PXD007206).

Cited by 13 publications

References 87 publications

Intermediate Filaments as Effectors of Cancer Development and Metastasis: A Focus on Keratins, Vimentin, and Nestin

Intermediate Filaments as Effectors of Cancer Development and Metastasis: A Focus on Keratins, Vimentin, and Nestin

High KRT8 Expression Independently Predicts Poor Prognosis for Lung Adenocarcinoma Patients

Validation study of MARCKSL1 as a prognostic factor in lymph node-negative breast cancer patients

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