Top

Published in:

01-10-2012 | Gastrointestinal Oncology

Keratin 17 Expression Correlates with Tumor Progression and Poor Prognosis in Gastric Adenocarcinoma

Authors: Munenori Ide, MD, PhD, Toshihide Kato, MD, Kyoichi Ogata, MD, PhD, Erito Mochiki, MD, PhD, Hiroyuki Kuwano, MD, PhD, Tetsunari Oyama, MD, PhD

Published in: Annals of Surgical Oncology | Issue 11/2012

Abstract

Background

Keratin 17 (K17) is regarded as a basal/myoepithelial cell keratin and is known to be inducible in activated keratinocytes. The high frequency of K17 expression in pancreaticobiliary nonmucinous adenocarcinoma or basal-like breast carcinoma has previously been described. However, its expression in gastric cancer (GC) is controversial.

Methods

We investigated the clinicopathological features and prognostic significance of 192 patients with GC by immunohistochemical staining of tissue microarrays. Analysis of epithelial markers including K17, K14, and K5/6, cell cycle-associated proteins p53, Ki-67, and 14-3-3 sigma, and mucinous phenotype markers including CD10, CDX2, MUC5AC, and MUC6 was performed.

Results

Cytoplasmic expression of K17 was observed in 95 (49.5 %) of 192 patients with GC. K17 expression positively correlated with lymph node metastasis (P = 0.003) and advanced stages of the disease (P = 0.014). K17 expression was significantly correlated with 14-3-3 sigma expression (P < 0.001) and CD10 expression (P = 0.015). The overall survival rates of patients with K17-positive GC were significantly lower than those with negative K17 expression (50.5 vs. 71.1 %, P = 0.004). Univariate analysis revealed that K17 expression confers a poor prognosis in patients with GC (P = 0.004), and it was also an independent prognostic factor in multivariate analysis (P = 0.049).

Conclusions

K17 expression is correlated with tumor progression in GC and may serve as a biomarker for poor prognosis.

Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893–917.PubMedCrossRef

Surveillance, Epidemiology, and End Results. SEER stat fact sheets: stomach. http://seer.cancer.gov/statfacts/html/stomach.html. Accessed 11 June 2012.

Moll R, Divo M, Langbein L. The human keratins: biology and pathology. Histochem Cell Biol. 2008;129:705–33.PubMedCrossRef

Karantza V. Keratins in health and cancer: more than mere epithelial cell markers. Oncogene. 2011;30:127–38.PubMedCrossRef

Moll R, Franke WW, Volc-Platzer B, Krepler R. Different keratin polypeptides in epidermis and other epithelia of human skin: a specific cytokeratin of molecular weight 46,000 in epithelia of the pilosebaceous tract and basal cell epitheliomas. J Cell Biol. 1982;95:229–85.CrossRef

Troyanovsky SM, Guelstein VI, Tchipysheva TA, Krutovskikh VA, Bannikov GA. Patterns of expression of keratin 17 in human epithelia: dependency on cell position. J Cell Sci. 1989;93:419–26.PubMed

Troyanovsky SM, Leube RE, Franke WW. Characterization of the human gene encoding cytokeratin 17 and its expression pattern. Eur J Cell Biol. 1992;59:127–37.PubMed

Chu PG, Schwarz RE, Lau SK, Yen Y, Weiss LM. Immunohistochemical staining in the diagnosis of pancreatobiliary and ampulla of Vater adenocarcinoma: application of CDX2, CK17, MUC1, and MUC2. Am J Surg Pathol. 2005;29:359–67.PubMedCrossRef

Goldstein NS, Bassi D. Cytokeratins 7, 17, and 20 reactivity in pancreatic and ampulla of vater adenocarcinomas. Percentage of positivity and distribution is affected by the cut-point threshold. Am J Clin Pathol. 2001;115:695–702.PubMedCrossRef

10.

Miettinen M, Nobel MP, Tuma BT, et al. Keratin 17: immunohistochemical mapping of its distribution in human epithelial tumors and its potential applications. Appl Immunohistochem. 1997;5:152–9.CrossRef

11.

Kim MA, Lee HS, Yang HK, Kim WH. Cytokeratin expression profile in gastric carcinomas. Hum Pathol. 2004;35:576–81.PubMedCrossRef

12.

Sarbia M, Fritze F, Geddert H, von Weyhern C, Rosenberg R, Gellert K. Differentiation between pancreaticobiliary and upper gastrointestinal adenocarcinomas: is analysis of cytokeratin 17 expression helpful? Am J Clin Pathol. 2007;128:255–9.PubMedCrossRef

13.

Ide M, Nakajima T, Asao T, Kuwano H. Inactivation of 14-3-3 sigma by hypermethylation is a rare event in colorectal cancers and its expression may correlate with cell cycle maintenance at the invasion front. Cancer Lett. 2004;207:241–9.PubMedCrossRef

14.

Barua RR, Uozaki H, Chong JM, et al. Phenotype analysis by MUC2, MUC5AC, MUC6, and CD10 expression in Epstein–Barr virus-associated gastric carcinoma. J Gastroenterol. 2006;41:733–9.PubMedCrossRef

15.

Almeida R, Silva E, Santos-Silva F, et al. Expression of intestine-specific transcription factors, CDX1 and CDX2, in intestinal metaplasia and gastric carcinomas. J Pathol. 2003;199:36–40.PubMedCrossRef

16.

Moll R, Moll I, Wiest W. Changes in the pattern of cytokeratin polypeptides in epidermis and hair follicles during skin development in human fetuses. Differentiation. 1982;23:170–8.PubMedCrossRef

17.

Jiang CK, Flanagan S, Ohtsuki M, Shuai K, Freedberg IM, Blumenberg M. Disease-activated transcription factor: allergic reactions in human skin cause nuclear translocation of STAT-91 and induce synthesis of keratin K17. Mol Cell Biol. 1994;14:4759–69.PubMed

18.

Wei KJ, Zhang L, Yang X, et al. Expression of cytokeratin 17 protein in oral squamous cell carcinoma in vitro and in vivo. Oral Dis. 2009;15:111–7.PubMedCrossRef

19.

Takahashi H, Shikata N, Senzaki H, Shintaku M, Tsubura A. Immunohistochemical staining patterns of keratins in normal oesophageal epithelium and carcinoma of the oesophagus. Histopathology. 1995;26:45–50.PubMedCrossRef

20.

Wetzels RH, Schaafsma HE, Leigh IM, et al. Laminin and type VII collagen distribution in different types of human lung carcinoma: correlation with expression of keratins 14, 16, 17 and 18. Histopathology. 1992;20:295–303.PubMedCrossRef

21.

Smedts F, Ramaekers F, Troyanovsky S, et al. Keratin expression in cervical cancer. Am J Pathol. 1992;141:497–511.PubMed

22.

Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98:10869–74.PubMedCrossRef

23.

Malzahn K, Mitze M, Thoenes M, Moll R. Biological and prognostic significance of stratified epithelial cytokeratins in infiltrating ductal breast carcinomas. Virchows Arch. 1998;433:119–29.PubMedCrossRef

24.

Thike AA, Iqbal J, Cheok PY, et al. Triple negative breast cancer: outcome correlation with immunohistochemical detection of basal markers. Am J Surg Pathol. 2010;34:956–64.PubMedCrossRef

25.

Larsson K, Eriksson C, Schwenk JM, et al. Characterization of PrEST-based antibodies towards human cytokeratin-17. J Immunol Methods. 2009;342:20–32.PubMedCrossRef

26.

Economescu MC, Necula LG, Dragu D, et al. Identification of potential biomarkers for early and advanced gastric adenocarcinoma detection. Hepatogastroenterology. 2010;57:1453–64.

27.

Pacelli F, Papa V, Caprino P, Sgadari A, Bossola M, Doglietto GB. Proximal compared with distal gastric cancer: multivariate analysis of prognostic factors. Am Surg. 2001;67:697–703.PubMed

28.

Tajima Y, Yamazaki K, Makino R, et al. Differences in the histological findings, phenotypic marker expressions and genetic alterations between adenocarcinoma of the gastric cardia and distal stomach. Br J Cancer. 2007;96:631–8.PubMedCrossRef

29.

Simpson PT, Gale T, Reis-Filho JS, et al. Distribution and significance of 14-3-3 sigma, a novel myoepithelial marker, in normal, benign, and malignant breast tissue. J Pathol. 2004;202:274–85.PubMedCrossRef

30.

O’Hare MJ, Ormerod MG, Monaghan P, Lane EB, Gusterson BA. Characterization in vitro of luminal and myoepithelial cells isolated from the human mammary gland by cell sorting. Differentiation. 1991;46:209–21.PubMedCrossRef

31.

Dabbs DJ, Chivukula M, Carter G, Bhargava R. Basal phenotype of ductal carcinoma in situ: recognition and immunohistologic profile. Mod Pathol. 2006;19:1506–11.PubMedCrossRef

32.

Dent R, Trudeau M, Pritchard KI, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res. 2007;13(15 Pt 1):4429–34.PubMedCrossRef

33.

Tanaka K, Hatada T, Kobayashi M, et al. The clinical implication of 14-3-3 sigma expression in primary gastrointestinal malignancy. Int J Oncol. 2004;25:1591–7.PubMed

34.

Muhlmann G, Ofner D, Zitt M, et al. 14-3-3 sigma and p53 expression in gastric cancer and its clinical applications. Dis Markers. 2010;29:21–9.PubMed

35.

Kim S, Wong P, Coulombe PA. A keratin cytoskeletal protein regulates protein synthesis and epithelial cell growth. Nature. 2006;441:362–5.PubMedCrossRef

36.

Ausch C, Buxhofer-Ausch V, Olszewski U, et al. Caspase-cleaved cytokeratin 18 fragment (M30) as marker of postoperative residual tumor load in colon cancer patients. Eur J Surg Oncol. 2009;35:1164–8.PubMedCrossRef

37.

Katsuragi K, Yashiro M, Sawada T, Osaka H, Ohira M, Hirakawa K. Prognostic impact of PCR-based identification of isolated tumour cells in the peritoneal lavage fluid of gastric cancer patients who underwent a curative R0 resection. Br J Cancer. 2007;97:550–6.PubMedCrossRef

38.

Xenidis N, Ignatiadis M, Apostolaki S, et al. Cytokeratin-19 mRNA-positive circulating tumor cells after adjuvant chemotherapy in patients with early breast cancer. J Clin Oncol. 2009;27:2177–84.PubMedCrossRef

39.

Knosel T, Emde V, Schluns K, Schlag PM, Dietel M, Petersen I. Cytokeratin profiles identify diagnostic signatures in colorectal cancer using multiplex analysis of tissue microarrays. Cell Oncol. 2006;28:167–75.PubMed

40.

Laakso M, Tanner M, Nilsson J, et al. Basoluminal carcinoma: a new biologically and prognostically distinct entity between basal and luminal breast cancer. Clin Cancer Res. 2006;12:4185–91.PubMedCrossRef

41.

Kim S, Coulombe PA. Intermediate filament scaffolds fulfill mechanical, organizational, and signaling functions in the cytoplasm. Genes Dev. 2007;21:1581–97.PubMedCrossRef

42.

Depianto D, Kerns ML, Dlugosz AA, Coulombe PA. Keratin 17 promotes epithelial proliferation and tumor growth by polarizing the immune response in skin. Nat Genet. 2010;42:910–4.PubMedCrossRef

43.

Shi X, Jin L, Dang E, Chang T, Feng Z, Liu Y, Wang G. IL-17A upregulates keratin 17 expression in keratinocytes through STAT1- and STAT3-dependent mechanisms. J Investig Dermatol. 2011;131:2401–8.PubMedCrossRef

44.

Bockelmann R, Horn T, Gollnick H, Bonnekoh B. Interferon-gamma-dependent in vitro model for the putative keratin 17 autoimmune loop in psoriasis: exploration of pharmaco- and gene-therapeutic effects. Skin Pharmacol Physiol. 2005;18:42–54.PubMedCrossRef

45.

Chang T, Sun L, Wang Y, et al. Inhibition of keratin 17 expression with antisense and RNAi strategies: exploring novel therapy for psoriasis. Exp Dermatol. 2011;20:555–60.PubMedCrossRef

Title: Keratin 17 Expression Correlates with Tumor Progression and Poor Prognosis in Gastric Adenocarcinoma
Authors: Munenori Ide, MD, PhD
Toshihide Kato, MD
Kyoichi Ogata, MD, PhD
Erito Mochiki, MD, PhD
Hiroyuki Kuwano, MD, PhD
Tetsunari Oyama, MD, PhD
Publication date: 01-10-2012
Publisher: Springer-Verlag
Published in: Annals of Surgical Oncology / Issue 11/2012
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-012-2437-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Keratin 17 Expression Correlates with Tumor Progression and Poor Prognosis in Gastric Adenocarcinoma

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 11/2012

Increasing Tumor Thickness is Associated with Recurrence and Poorer Survival in Patients with Merkel Cell Carcinoma

Surgical Approach and Outcomes in Patients with Lithium-Associated Hyperparathyroidism

Sentinel Lymph Node Biopsy for T1/T2 Oral Cavity Squamous Cell Carcinoma—A Prospective Case Series

The Beta2-Adrenergic Receptor is a Potential Prognostic Biomarker for Human Hepatocellular Carcinoma After Curative Resection

A Society in Transition: Presidential Remarks at the 65th Annual SSO Cancer Symposium

Systematic Pelvic and Aortic Lymphadenectomy in Advanced Ovarian Cancer Patients at the Time of Interval Debulking Surgery: A Double-Institution Case–Control Study