Proteomic analysis of cytokeratin isoforms uncovers association with survival in lung adenocarcinoma.
Cytokeratins (CK) are intermediate filaments whose expression is often altered in epithelial cancer. Systematic identification of lung adenocarcinoma proteins using two-dimensional polyacrylamide gel electrophoresis and mass spectrometry has uncovered numerous CK isoforms. In this study, 93 lung adenocarcinomas (64 stage I and 29 stage III) and 10 uninvolved lung samples were quantitatively examined for protein expression. Fourteen of 21 isoforms of CK 7, 8, 18, and 19 occurred at significantly higher levels (P < .05) in tumors compared to uninvolved adjacent tissue. Specific isoforms of the four types of CK identified correlated with either clinical outcome or individual clinical-pathological parameters. All five of the CK7 isoforms associated with patient survival represented cleavage products. Two of five CK7 isoforms (nos. 2165 and 2091), one of eight CK8 isoforms (no. 439), and one of three CK19 isoforms (no. 1955) were associated with survival and significantly correlated to their mRNA levels, suggesting that transcription underlies overexpression of these CK isoforms. Our data indicate substantial heterogeneity among CK in lung adenocarcinomas resulting from posttranslational modifications, some of which correlated with patient survival and other clinical parameters. Therefore, specific isoforms of individual CK may have utility as diagnostic or predictive markers in lung adenocarcinomas.
Gharib
Tarek G
TG
Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
Chen
Guoan
G
Wang
Hong
H
Huang
Chiang-Ching
CC
Prescott
Michael S
MS
Shedden
Kerby
K
Misek
David E
DE
Thomas
Dafydd G
DG
Giordano
Thomas J
TJ
Taylor
Jeremy M G
JM
Kardia
Sharon
S
Yee
John
J
Orringer
Mark B
MB
Hanash
Samir
S
Beer
David G
DG
D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D007633:Keratins / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D020033:Protein Isoforms; D020543:Proteome / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D015996:Survival Rate
D014408:Biomarkers, Tumor; D020033:Protein Isoforms; D020543:Proteome; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D007633:Keratins