Prognostic effect of hENT1, dCK and HuR expression by morphological type in periampullary adenocarcinoma, including pancreatic cancer

Jacob Elebro, Liv Ben Dror, Margareta Heby, Björn Nodin, Karin Jirström, Jakob Eberhard, Jacob Elebro, Liv Ben Dror, Margareta Heby, Björn Nodin, Karin Jirström, Jakob Eberhard

Abstract

Background: Putative biomarkers of gemcitabine response have been extensively studied in pancreatic cancer, but less so in other types of periampullary adenocarcinoma. The most studied biomarker is human equilibrative nucleoside transporter 1 (hENT1), and the activating enzyme deoxycytidine kinase (dCK) has also been linked to treatment response. The RNA-binding protein human antigen R (HuR) has been demonstrated to confer increased dCK levels in vitro and to predict gemcitabine response in vivo. Here, we investigated the prognostic impact of hENT1, dCK and HuR in pancreatobiliary (PB) and intestinal (I) type periampullary cancers, respectively.

Material and methods: Immunohistochemical expression of hENT1, dCK and HuR was evaluated in tissue microarrays with all primary tumours and 103 paired lymph node metastases from a consecutive retrospective cohort of 175 patients with resected periampullary adenocarcinomas.

Results: In patients with PB-type tumours, neither hENT1 nor dCK expression was prognostic. A high HuR cytoplasmic/nuclear ratio was associated with a significantly reduced five-year overall survival (OS) in patients receiving adjuvant gemcitabine (HR 2.07, 95% CI 1.03-4.17) but not in untreated patients (pinteraction = 0.028). In patients with I-type tumours receiving adjuvant chemotherapy, high dCK expression was significantly associated with a prolonged recurrence-free survival (RFS) (HR 0.09, 95% CI 0.01-0.73, pinteraction = 0.023). Furthermore, HuR expression was associated with a prolonged OS and RFS in unadjusted but not in adjusted analysis and hENT1 expression was an independent predictor of a prolonged RFS (HR 0.24, 95% CI 0.10-0.59), regardless of adjuvant treatment.

Conclusion: hENT1 expression is a favourable prognostic factor in I-type, but not in PB-type tumours. High dCK expression is a favourable prognostic factor in patients with I-type tumours receiving adjuvant treatment and a high cytoplasmic/nuclear HuR ratio is a negative prognostic factor in gemcitabine-treated PB-type tumours. Morphological subtype should always be considered in biomarker studies on periampullary cancer.

Figures

Figure 1.
Figure 1.
Examples of immunohistochemical staining of hENT1 (A–C), dCK (D–F) and HuR (G–I).
Figure 2.
Figure 2.
Kaplan–Meier curves of overall survival and recurrence-free survival in pancreatobiliary type tumours stratified by hENT1 (A,B), dCK (C,D) and HuR (E,F) expression and adjuvant gemcitabine.
Figure 3.
Figure 3.
Kaplan–Meier curves of overall survival and recurrence-free survival in intestinal type tumours, stratified by hENT1 (A,B), dCK (C,D) and HuR (E,F) expression and adjuvant chemotherapy.

References

    1. Wei CH, Gorgan TR, Elashoff DA, Hines OJ, Farrell JJ, Donahue TR. A meta-analysis of gemcitabine biomarkers in patients with pancreaticobiliary cancers. Pancreas. 2013;42:1303–10.
    1. Marechal R, Bachet JB, Mackey JR, Dalban C, Demetter P, Graham K. Levels of gemcitabine transport and metabolism proteins predict survival times of patients treated with gemcitabine for pancreatic adenocarcinoma. Gastroenterology. 2012;143:664–74e1–6.
    1. Farrell JJ, Elsaleh H, Garcia M, Lai R, Ammar A, Regine WF. Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. Gastroenterology. 2009;136:187–95.
    1. Greenhalf W, Ghaneh P, Neoptolemos JP, Palmer DH, Cox TF, Lamb RF. Pancreatic cancer hENT1 expression and survival from gemcitabine in patients from the ESPAC-3 trial. J Natl Cancer Inst. 2014;106:djt347.
    1. Perrone G, Morini S, Santini D, Rabitti C, Vincenzi B, Alloni R. Human equilibrative nucleoside transporter 1 and carcinoma of the ampulla of Vater: Expression differences in tumour histotypes. Eur J Histochem. 2010;54:e38.
    1. Santini D, Perrone G, Vincenzi B, Lai R, Cass C, Alloni R. Human equilibrative nucleoside transporter 1 (hENT1) protein is associated with short survival in resected ampullary cancer. Ann Oncol. 2008;19:724–8.
    1. Bouffard DY, Laliberte J, Momparler RL. Kinetic studies on 2',2'-difluorodeoxycytidine (Gemcitabine) with purified human deoxycytidine kinase and cytidine deaminase. Biochem Pharmacol. 1993;45:1857–61.
    1. Saiki Y, Yoshino Y, Fujimura H, Manabe T, Kudo Y, Shimada M. DCK is frequently inactivated in acquired gemcitabine-resistant human cancer cells. Biochem Biophys Res Commun. 2012;421:98–104.
    1. McAllister F, Pineda DM, Jimbo M, Lal S, Burkhart RA, Moughan J. dCK expression correlates with 5-fluorouracil efficacy and HuR cytoplasmic expression in pancreatic cancer: A dual-institutional follow-up with the RTOG 9704 trial. Cancer Biol Ther. 2014;15:688–98.
    1. Hinman MN, Lou H. Diverse molecular functions of Hu proteins. Cell Mol Life Sci. 2008;65:3168–81.
    1. Lopez de Silanes I, Lal A, Gorospe M. HuR: Post-transcriptional paths to malignancy. RNA Biol. 2005;2:11–13.
    1. Kotta-Loizou I, Giaginis C, Theocharis S. Clinical significance of HuR expression in human malignancy. Med Oncol. 2014;31:161, 1–19.
    1. Costantino CL, Witkiewicz AK, Kuwano Y, Cozzitorto JA, Kennedy EP, Dasgupta A. The role of HuR in gemcitabine efficacy in pancreatic cancer: HuR Up-regulates the expression of the gemcitabine metabolizing enzyme deoxycytidine kinase. Cancer Res. 2009;69:4567–72.
    1. Richards NG, Rittenhouse DW, Freydin B, Cozzitorto JA, Grenda D, Rui H. HuR status is a powerful marker for prognosis and response to gemcitabine-based chemotherapy for resected pancreatic ductal adenocarcinoma patients. Ann Surg. 2010;252:499–505.
    1. Yoo PS, Sullivan CA, Kiang S, Gao W, Uchio EM, Chung GG. Tissue microarray analysis of 560 patients with colorectal adenocarcinoma: High expression of HuR predicts poor survival. Ann Surg Oncol. 2009;16:200–7.
    1. Elebro J, Jirstrom K. Use of a standardized diagnostic approach improves the prognostic information of histopathologic factors in pancreatic and periampullary adenocarcinoma. Diagn Pathol. 2014;9:80, 1–10.
    1. Elebro J, Heby M, Gaber A, Nodin B, Jonsson L, Fristedt R. Prognostic and treatment predictive significance of SATB1 and SATB2 expression in pancreatic and periampullary adenocarcinoma. J Transl Med. 2014;12:289, 1–115.
    1. Fristedt R, Elebro J, Gaber A, Jonsson L, Heby M, Yudina Y. Reduced expression of the polymeric immunoglobulin receptor in pancreatic and periampullary adenocarcinoma signifies tumour progression and poor prognosis. PLoS One. 2014;9:e112728.
    1. Heby M, Elebro J, Nodin B, Jirstrom K, Eberhard J. Prognostic and predictive significance of podocalyxin-like protein expression in pancreatic and periampullary adenocarcinoma. BMC Clin Pathol. 2015;15:10.
    1. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM. Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst. 2005;97:1180–4.
    1. Mrena J, Wiksten JP, Thiel A, Kokkola A, Pohjola L, Lundin J. Cyclooxygenase-2 is an independent prognostic factor in gastric cancer and its expression is regulated by the messenger RNA stability factor HuR. Clin Cancer Res. 2005;11:7362–8.
    1. Santini D, Vincenzi B, Fratto ME, Perrone G, Lai R, Catalano V. Prognostic role of human equilibrative transporter 1 (hENT1) in patients with resected gastric cancer. J Cell Physiol. 2010;223:384–8.
    1. Poplin E, Wasan H, Rolfe L, Raponi M, Ikdahl T, Bondarenko I. Randomized, multicenter, phase II study of CO-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma: Including a prospective evaluation of the role of hENT1 in gemcitabine or CO-101 sensitivity. J Clin Oncol. 2013;31:4453–61.

Source: PubMed

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