Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with metastasis in most patients at diagnosis. The molecular mechanisms associated with its high malignancy have not been fully elucidated. This study investigated the clinicopathological significances of GPC3 and KRT19 expression in PDAC.
METHODS:
GPC3, KRT19, and CA19-9 protein expression were measured by immunohistochemistry.
RESULTS:
GPC3 and KRT19 protein levels were overexpressed in PDAC tumors compared to normal pancreatic tissues, benign pancreatic tissues, and peritumoral tissues (P< 0.01). The percentage of positive GPC3 and KRT19 expression were significantly higher in PDAC patients with larger tumor size, poorly differentiated tumor, lymph node metastasis, invasion, and TNM stage III/IV disease than in patients with small tumor size, well-differentiated tumor, no lymph node metastasis and invasion, as well as TNM stage I/II stage disease (P< 0.05 or P< 0.01). Benign pancreatic lesions with positive GPC3 and KRT19 protein expression exhibited dysplasia or intraepithelial neoplasia. Kaplan-Meier survival analysis showed that PDAC patients with positive GPC3 and KRT19 expression survived significantly shorter than patients with negative GPC3 and KRT19 expression (P < 0.05 or P< 0.001). Cox multivariate analysis revealed that positive GPC3 and KRT19 expression were independent poor prognosis factors in PDAC patients.
CONCLUSIONS:
GPC3 and KRT19 overexpression are associated with carcinogenesis, progression, and poor prognosis in patients with PDAC and a valuable biomarker for diagnosis of PDAC.
CanelM, SerrelsA, FrameMC, BruntonVG. E-cadherin-integrin crosstalk in cancer invasion and metastasis. J Cell Sci2013; 126: 393-401.
2.
ItohM, BissellMJ. The organization of tight junctions in epithelia: implications for mammary gland biology and breast tumorigenesis. J Mammary Gland Biol Neoplasia2003; 8: 449-62.
3.
QuailDF, JoyceJA. Microenvironmental regulation of tumor progression and metastasis. Nat Med2013; 19: 1423-37.
4.
SiegelR, NaishadhamD, JemalA. Cancer statistics, 2012. CA Cancer J Clin2012; 62; 10-29.
5.
HidalgoM. Pancreatic cancer. N Engl J Med2010; 362: 1605-17.
6.
SiegelR, MaJ, ZouZ, JemalA. Cancer statistics, 2014. CA2014; 64: 9-29.
7.
ZouZQ, DingYP, LongB, YuhJG, XuAL, LangZW, et al. Gpc-3 is a notable diagnostic, prognostic and a latent targeted therapy marker in hepatocellular carcinoma. Hepatogastroenterology2010; 57: 1285-90.
8.
ShirakawaH, KuronumaT, NishimuraY, HasebeT, NakanoM, GotohdaN, et al. Glypican-3 is a useful diagnostic marker for a component of hepatocellular carcinoma in human liver cancer. Int J Oncol2009; 34: 649-56.
9.
OhkarawaB, YamamotoTS, TadaM, UenoN. Role of glypican 4 in the regulation of convergent extension movements during gastrulation in xenopus laevis. Development2003; 130: 2129-38.
10.
TakaiH, KatoA, KinoshitaY, IshiguroT, TakaiY, OhtaniY, et al. Histopathological analyses of the antitumor activity of anti-glypican-3 antibody (GC33) in human liver cancer xenograft models: The contribution of macrophages. Cancer Biol Ther2009; 8: 930-8.
11.
MarianaIC, YunYX, CorrinneL, FilmusJ. GIypican-3 promotes the growth of hepatocellular carcinoma by stimulating canonical Wnt signaling. Cancer Res2005; 65: 6245-54.
12.
AnatelliF, ChuangST, YangXJ, WangHL. Value of Glypican 3 immunostaining in the diagnosis of hepatocellular carcinoma on needle biopsy. Am J Clin Pathol2008; 130: 219-23.
13.
OkolicsanyiRK, van WijnenAJ, CoolSM, et al. Heparan sulfate proteoglycans and human breast cancer epithelial cell tumorigenicity. J Cell Biochem2014; 115: 967-76.
14.
MoritaS, YoshidaA, GotoA, OtaS, TsutaK, YokozawaK, et al. High-grade lung adenocarcinoma with fetal lung-like morphology: clinicopathologic, immunohistochemical, and molecular analyses of 17 cases. Am J Surg Pathol2013; 37: 924-32.
15.
UshikuT, UozakiH, ShinozakiA, OtaS, MatsuzakaK, NomuraS, et al. Glypican 3-expressing gastric carcinoma: distinct subgroup unifying hepatoid, clear-cell, and alpha-fetoprotein-producing gastric carcinomas. Cancer Sci2009; 100: 626-32.
16.
JooEJ, WeyersA, LiG, GasimliL, LiL, ChoiWJ, LeeKB, et al. Carbohydrate-containing molecules as potential biomarkers in colon cancer. OMICS2014; 18: 231-41.
17.
MounajjedT, ZhangL, WuTT. Glypican-3 expression in gastrointestinal and pancreatic epithelial neoplasms. Hum Pathol2013; 44: 542-50.
18.
RogelMR, JaitovichA, RidgeKM. The Role of the Ubiquitin Proteasome Pathway in Keratin Intermediate Filament Protein Degradation. Thoracic Society2010; 1: 71-6.
19.
KabirNN, RönnstrandL, KaziJU. Keratin 19 expression correlates with poor prognosis in breast cancer. Mol Biol Rep2014; 41: 7729-35.
20.
PrasadML, PellegataNS, HuangY, NagarajaHN, de la ChapelleA, KloosRT. Galectin-3, fibronectin-1, CITED-1, HBME1 and cytokeratin-19 immunohistochemistry is useful for the differential diagnosis of thyroid tumors. Mod Pathol2005; 18: 48-57.
21.
GovaereO, KomutaM, BerkersJ, SpeeB, JanssenC, de LucaF, et al. Keratin 19: A key role player in the invasion of human hepatocellular carcinomas. Gut2014; 63: 674-85.
22.
de AlbuquerqueA, KubischI, BreierG, StammingerG, FersisN, EichlerA, et al. Multimarker gene analysis of circulating tumor cells in pancreatic cancer patients: a feasibility study. Oncology2012; 82: 3-10.
23.
OkamotoS, NiikuraH, NakabayashiK, HiyamaK, MatodaM, TakeshimaN, et al. Detection of sentinel lymph node metastases in cervical cancer: assessment of KRT19 mRNA in the one-step nucleic acid amplification (OSNA) method. Gynecol Oncol2013; 130: 530-6.
24.
PaivaF, Duarte-PereiraS, CostaVL, Ramalho-CarvalhoJ, PatrícioP, RibeiroFR, et al. Functional and epigenetic characterization of the KRT19 gene in renal cell neoplasms. DNA Cell Biol2011; 30: 85-90.
25.
LiuDC, YangZL, JiangS. Identification of PEG10 and TSG101 as carcinogenesis, progression, and poor-prognosis related biomarkers for gallbladder adenocarcinoma. Pathol Oncol Res2011; 17: 859-66.
26.
TopczewskyJ, SepichDS, MyersDC, WalkerC, AmoresA, LeleZ, et al. The Zebra fish glypican Knypek controls cell polarity during gastrulation movements of convergent extension. Dev Cell2001; 1: 251-64.
27.
GiovanellaL, BardelliD, TanziF, GaranciniS. Serum cytokeratin fragment 21.1 (CYFRA 21.1) as tumour marker for breast cancer: comparison with carbohydrate antigen 15.3 (CA 15.3) and carcinoembryonic antigen (CEA). Clin Chem Lab Med2002; 40: 298-303.
28.
NakataB, TakashimaT, OgawaY, IshikawaT, HirakawaK. Serum CYFRA 21-1 (cytokeratin-19 fragments) is a useful tumour marker for detecting disease relapse and assessing treatment efficacy in breast cancer. Br J Cancer2004; 91: 873-8.
29.
BidardFC, HajageD, BachelotT, DelalogeS, BrainE, CamponeM, et al. Assessment of circulating tumor cells and serum markers for progression-free survival prediction in metastatic breast cancer: a prospective observational study. Breast Cancer Res2012; 14: R29.
30.
AllegrettaM, FilmusJ. Therapeutic potential of targeting glypican-3 in hepatocellular carcinoma. Anticancer Agents Med Chem2011; 11: 543-8.
