Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 1/2010

01-01-2010 | Gastrointestinal Oncology

High Expression of Atypical Protein Kinase C λ/ι in Gastric Cancer as a Prognostic Factor for Recurrence

Authors: Ryo Takagawa, MD, Kazunori Akimoto, PhD, Yasushi Ichikawa, MD, PhD, Hirotoshi Akiyama, MD, PhD, Yasuyuki Kojima, MD, Hitoshi Ishiguro, PhD, Yoshiaki Inayama, MD, PhD, Ichiro Aoki, MD, PhD, Chikara Kunisaki, MD, PhD, Itaru Endo, MD, PhD, Yoji Nagashima, MD, PhD, Shigeo Ohno, PhD

Published in: Annals of Surgical Oncology | Issue 1/2010

Login to get access

Abstract

Background

The atypical protein kinase C lambda/iota (aPKCλ/ι) is involved in several signal transduction pathways that influence cell growth, apoptosis, and the establishment and maintenance of epithelial cell polarity. Overexpression of aPKCλ/ι has been reported in several cancers and been shown to be associated with oncogenesis. However, the expression and role of aPKCλ/ι in gastric cancer, one of the commonest cancers in Asia, have not so far been investigated. This study aimed to clarify the relationship between aPKCλ/ι expression and the clinicopathological features of gastric cancer.

Patients and Methods

Gastric adenocarcinoma samples were obtained from 177 patients who underwent gastrectomy at the Yokohama City University Hospital between 1999 and 2004. Expression of aPKCλ/ι and E-cadherin was examined immunohistochemically and compared with clinicopathological features of the tumors. Univariate and multivariate analyses were performed for both disease-specific and relapse-free survival.

Results

Overexpression of aPKCλ/ι protein was detected in 126 of the 177 (71.2%) gastric cancers. Immunohistological staining for aPKCλ/ι was stronger in gastric adenocarcinoma of intestinal type than diffuse type (p = 0.036), but was not correlated with E-cadherin expression. A multivariate analysis suggested that nodal metastasis and aPKCλ/ι overexpression were prognostic factors for disease recurrence.

Conclusions

Our results suggested that aPKCλ/ι overexpression was a strong prognostic factor for gastric adenocarcinoma recurrence. As well as being a new prognostic indicator, aPKCλ/ι is also likely to be a novel therapeutic target for gastric cancer.
Literature
1.
2.
Henson DE, Dittus C, Younes M, Nguyen H, Albores-Saavedra J. Differential trends in the intestinal and diffuse types of gastric carcinoma in the United States, 1973–2000: increase in the signet ring cell type. Arch Pathol Lab Med. 2004;128:765–70.PubMed
3.
Cunningham SC, Kamangar F, Kim MP, et al. Survival after gastric adenocarcinoma resection: eighteen-year experience at a single institution. J Gastrointest Surg. 2005;9:718–25.CrossRefPubMed
4.
Faycal J, Bessaguet C, Nousbaum JB, et al. Epidemiology and long term survival of gastric carcinoma in the French district of Finistere between 1984 and 1995. Gastroenterol Clin Biol. 2005;29:23–32.PubMedCrossRef
5.
6.
Koizumi W, Narahara H, Hara T, et al. S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol. 2008;9:215–21.CrossRefPubMed
7.
Ajani JA. Optimizing docetaxel chemotherapy in patients with cancer of the gastric and gastroesophageal junction: evolution of the docetaxel, cisplatin, and 5-fluorouracil regimen. Cancer. 2008;113:945–55.CrossRefPubMed
8.
Nishizuka Y. Protein kinase C and lipid signaling for sustained cellular responses. FASEB J. 1995;9:484–96.PubMed
9.
Suzuki A, Akimoto K, Ohno S. Protein kinase C lambda/iota (PKClambda/iota): a PKC isotype essential for the development of multicellular organisms. J Biochem. 2003;133:9–16.CrossRefPubMed
10.
Akimoto K, Mizuno K, Osada S, et al. A new member of the third class in the protein kinase C family, PKC lambda, expressed dominantly in an undifferentiated mouse embryonal carcinoma cell line and also in many tissues and cells. J Biol Chem. 1994;269:12677–83.PubMed
11.
Ohno S. Intercellular junctions and cellular polarity: the Par-aPKC complex, a conserved core cassette playing fundamental roles in cell polarity. Curr Opin Cell Biol. 2001;13:641–8.CrossRefPubMed
12.
Jamieson L, Carpenter L, Biden TJ, Fields AP. Protein kinase C iota activity is necessary for Bcr-Abl-mediated resistance to drug-induced apoptosis. J Biol Chem. 1999;274:3927–30.CrossRefPubMed
13.
Etienne-Manneville S, Hall A. Cell polarity: Par6, aPKC and cytoskeletal crosstalk. Curr Opin Cell Biol. 2003;1:67–72.CrossRef
14.
Moscat J, Diaz-Meco MT. The atypical protein kinase Cs Functional specificity mediated by specific protein adapters. EMBO Rep. 2000;1:399–403.CrossRefPubMed
15.
Akimoto K, Takahashi R, Moriya S, et al. EGF or PDGF receptors activate atypical PKC lambda through phosphatidylinositol 3-kinase. EMBO J. 1996;15:788–98.PubMed
16.
Akimoto K, Nakaya M, Yamanaka T, et al. Atypical protein kinase C lambda binds and regulates p70 S6 kinase. Biochem J. 1998;335:417–24.PubMed
17.
Moscat J, Diaz-Meco MT, Albert A, Campuzano S. Cell signaling and function organized by PB1 domain interactions. Mol Cell. 2006;23:631–40.CrossRefPubMed
18.
Regala RP, Weems C, Jamieson L, Copland JA, Thompson EA, Fields AP. Atypical protein kinase C ι plays a critical role in human lung cancer cell growth and tumorigenicity. J Biol Chem. 2005;280:31109–15.CrossRefPubMed
19.
Roderick PR, Capella W, Lee J, et al. Atypical protein kinase C ι is an oncogene in human non-small cell lung cancer. Cancer Res. 2005;65:8905–11.CrossRef
20.
Weichert W, Gekeler V, Denkert C, Dietel M, Hauptmann S. Protein kinase C isoform expression in ovarian carcinoma correlates with indicators of poor prognosis. Int J Oncol. 2003;23:633–9.PubMed
21.
Eder AM, Sui X, Rosen DG, et al. Atypical PKC iota contributes to poor prognosis through loss of apical-basal polarity and cyclin E overexpression in ovarian cancer. Proc Natl Acad Sci USA. 2005;102:12519–24.CrossRefPubMed
22.
Zhang L, Huang J, Yang N, et al. Integrative genomic analysis of protein kinase C (PKC) family identifies PKC iota as a biomarker and potential oncogene in ovarian carcinoma. Cancer Res. 2006;66:4627–35.CrossRefPubMed
23.
Murray NR, Jamieso L, Yu W, et al. Protein kinase C iota is required for Ras transformation and colon carcinogenesis in vivo. J Cell Biol. 2004;164:797–802.CrossRefPubMed
24.
Li Q, Wang JM, Liu C, Xiao BL, Lu JX, Zou SQ. Correlation of aPKC-iota and E-cadherin expression with invasion and prognosis of cholangiocarcinoma. Hepatobiliary Pancreat Dis Int. 2008;7:70–5.PubMed
25.
Kojima Y, Akimoto K, Nagashima Y, et al. The overexpression and altered localization of the atypical protein kinase C lambda/iota in breast cancer correlates with the pathologic type of these tumors. Hum Pathol. 2008;39:824–31.CrossRefPubMed
26.
Yeaman C, Grindstaff KK, Nelson WJ. New perspectives on mechanisms involved in generating epithelial cell polarity. Physiol Rev. 1999;79:73–98.PubMed
27.
Onder TT, Gupta PB, Mani SA, Yang J, Lander ES, Weinberg RA. Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res. 2008;68:3645–54.CrossRefPubMed
28.
Jawhari A, Johnson S, Poole S, Browne P, Pignatelli M, Farthing MJ. Abnormal immunoreactivity of the E-cadherin-catenin complex in gastric carcinoma: relationship with patients survival. Gastroenterology. 1997;112:46–54.CrossRefPubMed
29.
Yonemura Y, Endou Y, Kimura K, et al. Inverse expression of S100A4 and E-cadherin is associated with metastatic potential in gastric cancer. Clin Cancer Res. 2000;6:4234–42.PubMed
30.
Shimada Y, Yamasaki S, Hashimoto Y, et al. Clinical significance of dysadherin expression in gastric cancer patients. Clin Cancer Res. 2004;10:2818–23.CrossRefPubMed
31.
Hamilton SR, Aaltonen LA. Pathology and genetics of tumours of the digestive system. Lyon: IARCP Press; 2000. p. 39–52.
32.
Sobin LH, Wittekind, CH. TNM: classification of malignant tumours, 6th edn. The International Union against Cancer (UICC); 2003.
33.
Suzuki A, Ishiyama C, Hashiba K, Shimizu M, Ebnet K, Ohno S. aPKC kinase activity is required for the asymmetric differentiation of the premature junctional complex during epithelial cell polarization. J Cell Sci. 2002;115:3565–73.CrossRefPubMed
34.
Yamanaka T, Horikoshi Y, Suzuki A, et al. PAR-6 regulates aPKC activity in a novel way and mediates cell-cell contact-induced formation of the epithelial junctional complex. Genes Cells. 2001;6:721–31.CrossRefPubMed
35.
36.
Uberall F, Hellbert K, Kampfer S, et al. Evidence that atypical protein kinase C-lambda and atypical protein kinase C-zeta participate in Ras-mediated reorganization of the F-actin cytoskeleton. J Cell Biol. 1999;144:413–25.CrossRefPubMed
37.
Kampfer S, Windegger M, Hochholdinger F, Schwaiger W, Pestell RG, Baier G, et al. Protein kinase C isoforms involved in the transcriptional activation of cyclin D1 by transforming Ha-Ras. J Biol Chem. 2001;276:42834–42.CrossRefPubMed
38.
Murray NR, Jamieson L, Yu W, et al. Protein kinase C iota is required for Ras transformation and colon carcinogenesis in vivo. J Cell Biol. 2004;164:797–802.CrossRefPubMed
39.
Shino Y, Watanabe A, Yamada Y, et al. Clinicopathologic evaluation of immunohistochemical E-cadherin expression in human gastric carcinomas. Cancer. 1995;76:2193–201.CrossRefPubMed
40.
Ougolkov A, Yamashita K, Bilim V, Takahashi Y, Mai M, Minamoto T. Abnormal expression of E-cadherin, beta-catenin, and c-erbB-2 in advanced gastric cancer: its association with liver metastasis. Int J Colorectal Dis. 2003;18:160–6.PubMed
41.
Lu Y, Jamieson L, Brasier AR, Fields AP. NF-kappaB/RelA transactivation is required for atypical protein kinase C iota-mediated cell survival. Oncogene. 2001;20:4777–92.CrossRefPubMed
42.
43.
Fields AP, Regala RP. Protein kinase C iota: human oncogene, prognostic marker and therapeutic target. Pharmacol Res. 2007;55:487–97.CrossRefPubMed
44.
Regala RP, Thompson EA, Fields AP. Atypical protein kinase C iota expression and aurothiomalate sensitivity in human lung cancer cells. Cancer Res. 2008;68:5888–95.CrossRefPubMed
45.
Fields AP, Murray NR. Protein kinase C isozymes as therapeutic targets for treatment of human cancers. Adv Enzyme Regul. 2008;48:166–78.CrossRefPubMed
46.
Stallings-Mann M, Jamieson L, Regala RP, Weems C, Murray NR, Fields AP. A novel small-molecule inhibitor of protein kinase C iota blocks transformed growth of non-small-cell lung cancer cells. Cancer Res. 2006;66:1767–74.CrossRefPubMed
Metadata
Title
High Expression of Atypical Protein Kinase C λ/ι in Gastric Cancer as a Prognostic Factor for Recurrence
Authors
Ryo Takagawa, MD
Kazunori Akimoto, PhD
Yasushi Ichikawa, MD, PhD
Hirotoshi Akiyama, MD, PhD
Yasuyuki Kojima, MD
Hitoshi Ishiguro, PhD
Yoshiaki Inayama, MD, PhD
Ichiro Aoki, MD, PhD
Chikara Kunisaki, MD, PhD
Itaru Endo, MD, PhD
Yoji Nagashima, MD, PhD
Shigeo Ohno, PhD
Publication date
01-01-2010
Publisher
Springer-Verlag
Published in
Annals of Surgical Oncology / Issue 1/2010
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-009-0708-x

Other articles of this Issue 1/2010

Annals of Surgical Oncology 1/2010 Go to the issue

Gastrointestinal Oncology

Increased Intratumoral Lymphatic Vessel Density Correlates with Lymph Node Metastasis in Early Gastric Carcinoma

Melanomas

Sentinel Lymph Node Biopsy in Pediatric and Adolescent Cutaneous Melanoma Patients

Gastrointestinal Oncology

Different Patterns of Lymphatic Spread of Sigmoid, Rectosigmoid, and Rectal Cancers

Breast Oncology

Nipple-Sparing Mastectomy: Overcoming Oncological Outcomes Challenges

Gastrointestinal Oncology

Limitations of Isolated Tumor Cells in Gastric Cancer: Heterogeneity Requests Systems Biology Approaches Towards Personalized Medicine

Gynecologic Oncology

Prognostic Impact of Additional Extended Surgical Procedures in Advanced-Stage Primary Ovarian Cancer