Prostate Cancer Cell Surface-Associated Keratin 8 and Its Implications for Enhanced Plasmin Activity

Kuchma, Melissa Hirsch; Kim, Joo Hee; Muller, Mark T.; Arlen, Philip A.

doi:10.1007/s10930-011-9388-z

Cited by 13 publications

(10 citation statements)

References 53 publications

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“…However, the effect of RAS on cytokeratin 8 was not observed in all cell lines examined as 293T cells transfected with oncogenic HRAS failed to show an increased expression of cytokeratin 8, whereas S100A10 and annexin A2 expression were elevated in these cells (Supplementary Figure S3). Cytokeratin 8 expression has been reported on the surface of cancer cells and only in certain epithelial cells [48, 54–56] and to be upregulated in HRAS expressing epidermal cells [57]. Nonetheless, the loss of cytokeratin 8 expression rather than its upregulation is associated with metastasis and chemoresistance [58].…”

Section: Resultsmentioning

confidence: 99%

Cell surface protease activation during RAS transformation: Critical role of the plasminogen receptor, S100A10

et al. 2016

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The link between oncogenic RAS expression and the acquisition of the invasive phenotype has been attributed to alterations in cellular activities that control degradation of the extracellular matrix. Oncogenic RAS-mediated upregulation of matrix metalloproteinase 2 (MMP-2), MMP-9 and urokinase-type plasminogen activator (uPA) is critical for invasion through the basement membrane and extracellular matrix. The uPA converts cell surface-bound plasminogen to plasmin, a process that is regulated by the binding of plasminogen to specific receptors on the cell surface, however, the identity of the plasminogen receptors that function in this capacity is unclear. We have observed that transformation of cancer cells with oncogenic forms of RAS increases plasmin proteolytic activity by 2- to 4-fold concomitant with a 3-fold increase in cell invasion. Plasminogen receptor profiling revealed RAS-dependent increases in both S100A10 and cytokeratin 8. Oncogenic RAS expression increased S100A10 gene expression which resulted in an increase in S100A10 protein levels. Analysis with the RAS effector-loop mutants that interact specifically with Raf, Ral GDS pathways highlighted the importance of the RalGDS pathways in the regulation of S100A10 gene expression. Depletion of S100A10 from RAS-transformed cells resulted in a loss of both cellular plasmin generation and invasiveness. These results strongly suggest that increases in cell surface levels of S100A10, by oncogenic RAS, plays a critical role in RAS-stimulated plasmin generation, and subsequently, in the invasiveness of oncogenic RAS expressing cancer cells.

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Section: Resultsmentioning

confidence: 99%

Cell surface protease activation during RAS transformation: Critical role of the plasminogen receptor, S100A10

et al. 2016

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“…Unlike other endocytotic receptors, such as mannose receptor or CLEC9A, DEC205 usually targets to late endosomes and lysosomes (14,43); thus, DEC205 may also bind keratins on cell debris in phagosomes or early endosomes and transport them to late endosomes and lysosomes for more efficient antigen presentation. It is noteworthy that keratins are not only expressed inside cells, they are also found on the surface of some cell types such as carcinoma cells (30,(48)(49)(50). Evidence shows that extracellular acidification is usually associated with inflammation and tumorigenesis and is treated as a danger signal by the immune system (51)(52)(53).…”

Section: Discussionmentioning

confidence: 99%

Keratin mediates the recognition of apoptotic and necrotic cells through dendritic cell receptor DEC205/CD205

Cao

Chang

Shi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Clearance of dead cells is critical for maintaining homeostasis and prevents autoimmunity and inflammation. When cells undergo apoptosis and necrosis, specific markers are exposed and recognized by the receptors on phagocytes. DEC205 (CD205) is an endocytotic receptor on dendritic cells with antigen presentation function and has been widely used in immune therapies for vaccine generation. It has been shown that human DEC205 recognizes apoptotic and necrotic cells in a pH-dependent fashion. However, the natural ligand(s) of DEC205 remains unknown. Here we find that keratins are the cellular ligands of human DEC205. DEC205 binds to keratins specifically at acidic, but not basic, pH through its N-terminal domains. Keratins form intermediate filaments and are important for maintaining the strength of cells and tissues. Our results suggest that keratins also function as cell markers of apoptotic and necrotic cells and mediate a pH-dependent pathway for the immune recognition of dead cells. T he immune system is responsible for removing self-antigens such as dead cells to maintain tissue homeostasis and prevent autoimmunity (1-3). Dead cells are recognized and engulfed by phagocytes through their cell surface receptors (4), leading to either immune activation or tolerance (5-8). A number of receptors have been found to be able to mediate the clearance of dead cells (3); for example, CD14 (9), CD36 (10), integrin (11), PtdSerR (12), CLEC9A (13-15), and TIM receptor family members (16). Among known dead cell markers, phosphatidylserine (PS) is the most common one that can be recognized by several receptors such as CD36, PtdSerR, and TIM receptors, and acts as an "eatme" signal for phagocytes mediating dead cell clearance (4). Other than PS, several cellular proteins have also been found to be able to perform the similar function. For example, actin filaments can be recognized by CLEC9A as a damaged cell marker (13, 15). The recognition of different dead cell markers by phagocytes provides an efficient way to remove cell debris completely.Keratins are important cytoskeletal components and form intermediate filaments in cytoplasm. There are 54 known members in the keratin family that are divided into two types based on their isoelectric points and sequences (17). Keratin monomers can assemble into bundles first and then form fibrous filaments ∼10 nm in diameter, which act as a scaffold and provide mechanical support for maintaining the strength and toughness of cells and tissues (18,19). Recently, evidence has accumulated showing that keratins play physiological roles in addition to their structural functions, for example, in cell growth, proliferation, mobility, apoptosis, and tumorigenesis (18,20,21). DEC205 (CD205 or Ly75, molecular mass of 205 kDa) is an endocytotic receptor highly expressed on dendritic cells and thymic epithelial cells (8,22) and capable of inducing either tolerance or immunity in the absence or presence of inflammatory stimuli (23). DEC205 belongs to the mannose receptor family (24), which includes...

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“…KRT8, which is sensitive to TNF-dependent epithelial apoptosis, 53 has been proved to be an important distinguishing marker in prostate cancer. 54 Furthermore, we observed that both lnc-SNURF-1 and KRT8 showed significantly increased expression in the re-annotated exon array (Fig. 7B) and other RNA-seq data (Fig.…”

Section: Systematic Evaluation Of Predicted Cancer-related Lncrnasmentioning

confidence: 64%

Identification of cancer-related lncRNAs through integrating genome, regulome and transcriptome features

Zhao

Liu

et al. 2015

Mol. BioSyst.

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LncRNAs have become rising stars in biology and medicine, due to their versatile functions in a wide range of important biological processes and active roles in various human cancers. Here, we developed a computational method based on the naïve Bayesian classifier method to identify cancer-related lncRNAs by integrating genome, regulome and transcriptome data, and identified 707 potential cancer-related lncRNAs. We demonstrated the performance of the method by ten-fold cross-validation, and found that integration of multi-omic data was necessary to identify cancer-related lncRNAs. We identified 707 potential cancer-related lncRNAs and our results showed that these lncRNAs tend to exhibit significant differential expression and differential DNA methylation in multiple cancer types, and prognosis effects in prostate cancer. We also found that these lncRNAs were more likely to be direct targets of TP53 family members than others. Moreover, based on 147 lncRNA knockdown data in mice, we validated that four of six mouse orthologous lncRNAs were significantly involved in many cancer-related processes, such as cell differentiation and the Wnt signaling pathway. Notably, one lncRNA, lnc-SNURF-1, which was found to be associated with TNF-mediated signaling pathways, was up-regulated in prostate cancer and the protein-coding genes affected by knockdown of the lncRNA were also significantly aberrant in prostate cancer patients, suggesting its probable importance in tumorigenesis. Taken together, our method underlines the power of integrating multi-omic data to uncover cancer-related lncRNAs.

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Prostate Cancer Cell Surface-Associated Keratin 8 and Its Implications for Enhanced Plasmin Activity

Cited by 13 publications

References 53 publications

Cell surface protease activation during RAS transformation: Critical role of the plasminogen receptor, S100A10

Cell surface protease activation during RAS transformation: Critical role of the plasminogen receptor, S100A10

Keratin mediates the recognition of apoptotic and necrotic cells through dendritic cell receptor DEC205/CD205

Identification of cancer-related lncRNAs through integrating genome, regulome and transcriptome features

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