Cytokeratin-18 fragments predict treatment response and overall survival in gastric cancer in a randomized controlled trial

Nagel, Michael; Schulz, Julia; Maderer, Annett; Goepfert, Katrin; Gehrke, Nadine; Thomaidis, Thomas; Thuss‐Patience, Peter; Al-Batran, S.; Hegewisch‐Becker, Susanna; Grimminger, Peter; Galle, Peter R.; Möhler, Markus; Schattenberg, Jörn M.

doi:10.1177/1010428318764007

Cited by 16 publications

(18 citation statements)

References 22 publications

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“…Besides, Kilic-Baygutalp et al [17] found KRT18 expression was positively associated with clinical stage, tumor stage, and metastasis stage in patients with esophageal cancer. In gastric cancer, high KRT18 expression was suggested to be associated with positive lymph nodes, advanced clinical stage, and chemoresistance [33,34].…”

Section: Discussionmentioning

confidence: 99%

KRT18 is correlated with the malignant status and acts as an oncogene in colorectal cancer

Zhang

2019

Bioscience Reports

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Keratin 18 (KRT18) has been suggested to be overexpressed in most types of human tumor, but the expression pattern of KRT18 in colorectal cancer (CRC) remained unknown. In our research, KRT18 protein expression was markedly increased in CRC cancer tissues and cell lines compared with adjacent normal colorectal tissues and normal colonic epithelial cell line, respectively. Meanwhile, we observed high KRT18 expression was associated with advanced clinical stage, deep tumor invasion, lymph node metastasis, distant metastasis, poor differentiation and unfavorable prognosis in CRC patients. Multivariate Cox regression analysis showed high expression of KRT18 was an unfavorable independent predictor for overall survival in CRC patients. The in vitro studies indicated down-regulation of KRT18 expression depressed CRC cell viability, migration and invasion. In conclusion, KRT18 serves as an oncogenic role in CRC progression and may be a therapeutic target for promoting CRC patients’ prognosis.

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Section: Discussionmentioning

confidence: 99%

KRT18 is correlated with the malignant status and acts as an oncogene in colorectal cancer

Zhang

2019

Bioscience Reports

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“…Full-length CK18 (M65) and the caspase-cleaved fragment (M30) are recognized as useful markers in clinical diagnosis and prognostic evaluation (18) and recently, the important regulatory role of CK18 has also attracted attention. A recent study revealed that CK18 could associate with histone H3, leading to aberrant expression of histone deacetylase in hepatocellular carcinoma (52).…”

Section: Discussionmentioning

confidence: 99%

“…Keratins 8, 18 and 19 (CK8, CK18 and CK19), which are the most abundant keratins in simple epithelial cells, are extensively used as the diagnostic markers (17,18). CK18, also known as KRT18, and its caspase-cleaved fragment can be released into the circulation and are indicative of epithelial cell necrosis and apoptosis, respectively.…”

Section: Introductionmentioning

confidence: 99%

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Cytokeratin 18 regulates the transcription and alternative splicing of apoptotic‑related genes and pathways in HeLa cells

Cheng

Huang

Zhou³

et al. 2019

Oncol Rep

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Cytokeratin 18 (CK18), one of the major components of intermediate filaments (IF) in simple epithelial cells, undergoes caspase-mediated cleavage upon epithelial cell necrosis and apoptosis. CK18 has been used as a biomarker of several cancers and has been reported to be dysregulated in cervical cancers. The effects of dysregulated expression of CK18 at a molecular level are, however, unclear. In the present study, the function of CK18 in HeLa cells, a cell line derived from a cervical cancer cells, was investigated using shRNA knockdown. Reduced levels of CK18 led to a significant decrease in cell apoptosis, compared with control cells. Notably, RNA-seq analysis of the transcriptomes of HeLa cells, with or without CK18 knockdown, revealed that genes in the NF-κB pathway, and certain apoptosis pathways, were under global transcriptional and alternative splicing regulation. Quantitative RT-PCR confirmed the CK18-regulated transcription of apoptotic genes FAS and FADD , as well as immune genes CXCL2 and CD79B , in addition to alternative splicing of FAS and CTNNB1 . Western blot analysis further revealed that CK18 knockdown led to reduced expression of CASP8. In conclusion, the present study indicated that CK18 played a role in apoptosis, which may be mediated via a feed-back regulation loop and may involve regulation of transcription and alternative splicing of a number of genes in apoptotic pathways.

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“…8 (72.7 %) of the studies provided data of M30 expression, and 8 (72.7%) of the studies provided data of M65 expression, while 5 (45.5 %) of them provided data of both. Four (36.4 %) of the studies were in gastric cancer [18][19][20][21], two (18.2 %) studies in HCC [22,23], three (27.3 %) studies in colorectal cancer [24][25][26], and two (18.2 %) in pancreatic cancer [27,28]. The cut-off value of M30 and M65 varies in different studies, ranging from 59.1 U/L to 887 U/L, and from 199.3 U/L to1614 U/L, respectively.…”

Section: Literature Detailsmentioning

confidence: 99%

Prognostic value of non-invasive serum Cytokeratin 18 detection in gastrointestinal cancer: a meta-analysis

et al. 2019

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Background: Gastrointestinal cancer is one of the most common neoplasms. Cytokeratin 18(CK18) is widely expressed in many different organs and cancers. Emerging data suggested conflicting results about the role of CK18 during carcinogenesis. The aim of this study is to systematically review the prognostic value of circulating CK18 (M65) and caspase-Cleaved CK18 (M30) in digestive cancers. Materials and Methods: We searched major database for manuscripts reporting the effect of pretreatment CK18 on survival of digestive cancer patients. Revman5.3 and R were the software used for analysis. Pooled multivariable-adjusted hazard ratios (HR) for overall survival (OS) were calculated in all patients and many different subgroup analyses by stratifying on tumor type, metastasis stage, and ethnicity. Results: 11 original studies were included for analysis. A low level of M30 and M65 were shown to be a protective factor for all cancer patients (HR 0.49, 95%CI 0.33-0.73, P=0.0003; HR 0.48, 95% CI 0.32-0.70, P =0.0001, respectively). The low M30 remained to be a protective factor for metastasized cancer patients while M65 had no statistically significant correlation with prognosis. Conclusions: Non-invasive total and cleaved CK18 level detection by ELISA could be potentially a useful predictor of prognosis of digestive cancer patients. Further studies are warranted to investigate the molecular mechanisms of CK18.

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Cytokeratin-18 fragments predict treatment response and overall survival in gastric cancer in a randomized controlled trial

Abstract: The cytokeratin-18 fragment M30 at day 14 identifies patients that fail to second- or third-line therapy for advanced gastric cancer. Validation of this non-invasive biomarker in gastric cancer is warranted.

Cited by 16 publications

References 22 publications

KRT18 is correlated with the malignant status and acts as an oncogene in colorectal cancer

KRT18 is correlated with the malignant status and acts as an oncogene in colorectal cancer

Cytokeratin 18 regulates the transcription and alternative splicing of apoptotic‑related genes and pathways in HeLa cells

Prognostic value of non-invasive serum Cytokeratin 18 detection in gastrointestinal cancer: a meta-analysis

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