Abstract
Purpose
To identify biological markers related to the progression and prognosis of GBC.
Methods
The expressions of pyruvate kinase isoenzyme type M2 (PKM2) and activin A receptor type IC (ACVR 1C) in 46 squamous cell/adenosquamous carcinomas (SC/ASC) and 80 adenocarcinomas (AC) were examined using immunohistochemistry.
Results
Positive PKM2 and negative ACVR 1C expressions were significantly associated with lymph node metastasis, invasion and TNM stage of SC/ASCs and ACs. Univariate Kaplan–Meier analysis showed that either elevated PKM2 or loss of ACVR 1C expression significantly correlated with shorter average survival times in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive PKM2 expression and loss of ACVR 1C expression were poor prognosis biomarkers in both SC/ASC and AC patients.
Conclusions
Our study suggested that PKM2 overexpression is a marker of metastasis, invasion and poor prognosis of GBC. ACVR 1C is a tumor suppressor, and lowered ACVR 1C expression is an important marker for the metastasis, invasion, and prognosis of GBC.
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References
Jayaraman S, Jarnagin WR. Management of gallbladder cancer. Gastroenterol Clin North Am. 2010;39:331–42.
Hawkins WG, DeMatteo RP, Jarnagin WR, Ben-Porat L, Blumgart LH, Fong Y. Jaundice predicts advanced disease and early mortality in patients with gallbladder cancer. Ann Surg Oncol. 2004;11:310–5.
de Aretxabala X, Roa I, Burgos L, Losada H, Roa JC, Mora J, et al. Gallbladder cancer: an analysis of a series of 139 patients with restricted to the subserosal layer. J Gastrointest Surg. 2006;10:186–92.
Ootani T, Shirai Y, Tsukada K, Muto T. Relationship between gallbladder carcinoma and the segmental type of adenomyomatosis of the gallbladder. Cancer. 1992;69:2647–52.
Roa JC, Tapia O, Cakir A, Basturk O, Dursun N, Akdemir D, et al. Squamous cell and adenosquamous carcinomas of the gallbladder: clinicopathological analysis of 34 cases identified in 606 carcinomas. Mod Pathol. 2011;24:1069–78.
Mazurek S. Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells. Int J Biochem Cell Biol. 2011;43:969–80.
Mazurek S, Boschek CB, Hugo F, Eigenbrodt E. Pyruvate kinase type M2 and its role in tumor growth and spreading. Semin Cancer Biol. 2005;15:300–8.
Spoden GA, Mazurek S, Morandell D, Bacher N, Ausserlechner MJ, Jansen-Dürr P, et al. Isotype-specific inhibitors of the glycolytic key regulator pyruvate kinase subtype M2 moderately decelerate tumor cell proliferation. Int J Cancer. 2008;123:312–21.
Jiang K, He B, Lai L, Chen Q, Liu Y, Guo Q, et al. Cyclosporine A inhibits breast cancer cell growth by downregulating the expression of pyruvate kinase subtype M2. Int J Mol Med. 2012;30:302–8.
Watanabe R. Activin receptor-like kinase and the insulin gene. Vitam Horm. 2011;85:1–27.
Tsuchida K, Nakatani M, Uezumi A, Murakami T, Cui X. Signal transduction pathway through activin receptors as a therapeutic target of musculoskeletal diseases and cancer. Endocr J. 2008;55:11–21.
Angenete E, Langenskiöld M, Palmgren I, Falk P, Oresland T, Ivarsson ML. Transforming growth factor beta-1 in rectal tumor, mucosa and plasma in relation to radiotherapy and clinical outcome in rectal cancer patients. Int J Colorectal Dis. 2007;22:1331–8.
Joshi A, Cao D. TGF-beta signaling, tumor microenvironment and tumor progression: the butterfly effect. Front Biosci. 2010;15:180–94.
Liu DC, Yang ZL, Jiang S. Identification of PEG10 and TSG101 as carcinogenesis, progression, and poor-prognosis related biomarkers for gallbladder adenocarcinoma. Pathol Oncol Res. 2011;17:859–66.
Kondo M, Dono K, Sakon M, Shimizu J, Nagano H, Nakamori S, et al. Adenosquamous carcinoma of the gallbladder. Hepatogastroenterology. 2002;49:1230–4.
Mazurek S. Pyruvate kinase type M2: a key regulator within the tumour metabolome and a tool for metabolic profiling of tumours. Ernst Schering Found Symp Proc. 2007;4:99–124.
Hoda MA, Münzker J, Ghanim B, Schelch K, Klikovits T, Laszlo V, et al. Suppression of activin A signals inhibits growth of malignant pleural mesothelioma cells. Br J Cancer. 2012;107:1978–86.
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Li, J., Yang, Z., Zou, Q. et al. PKM2 and ACVR 1C are prognostic markers for poor prognosis of gallbladder cancer. Clin Transl Oncol 16, 200–207 (2014). https://doi.org/10.1007/s12094-013-1063-8
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DOI: https://doi.org/10.1007/s12094-013-1063-8