Abstract
BackgroundHigh-mobility group box 1 (HMGB1) is a nucleoprotein that is related to inflammation. It has been implicated in a variety of biologically important processes, including transcription, DNA repair, differentiation, development, and extracellular signaling. Recently, its important role in the process of tumor invasion, metastasis, and resistance to anti-cancer therapies has been demonstrated. In this study, we aimed to investigate the correlation of HMGB1 expression and resistance of rectal cancer patients to chemoradiotherapy (CRT) prior to curative operation.MethodsWe retrospectively reviewed the data of 75 lower rectal cancer patients without complete pathological response who had received preoperative CRT and had undergone curative resection at the University of Tokyo Hospital between May 2003 and June 2010. HMGB1 expression in surgically resected specimens was evaluated using immunohistochemical detection and specimens were classified into high or low HMGB1 expression groups. Clinicopathologic features, degree of tumor reduction, regression of tumor grade, and patient survival were compared between the groups using non-paired Student’s t-tests and Kaplan-Meier analysis.ResultsA total of 52 (69.3%) patients had high HMGB1 expression, and 23 (30.7%) had low expression. HMGB1 expression was significantly correlated with histologic type (P = 0.02), lymphatic invasion (P = 0.02), and venous invasion (P = 0.05). Compared to patients with low HMGB1 expression, those with high expression had a poorer response to CRT, in terms of tumor reduction ratio (42.2 versus 28.9%, respectively; P <0.01) and post-CRT histological tumor regression grade (56.5 versus 30.8% grade 2; respectively; P = 0.03). However, no significant correlation was found between HMGB1 expression and recurrence-free and overall survival rates.ConclusionsHMGB1 expression may be one of the key factors regulating the response of rectal cancer to preoperative CRT in terms of tumor invasiveness and resistance to therapy.
Highlights
High-mobility group box 1 (HMGB1) is a nucleoprotein that is related to inflammation
HMGB1 promotes inflammation by binding to the receptors, such as the receptor for advanced glycation end-products (RAGE), Toll-like receptor (TLR) 2, and Toll-like receptor 4 (TLR-4), which are expressed in a variety of cells including monocytes, macrophages, and endothelial cells [7,9,10,11,12]
Clinicopathological features were analyzed on the basis of the TNM Classification of Malignant Tumors, Seventh edition, using the International Union Against Cancer (UICC) [37] and World Health Organization (WHO) histological criteria [38]
Summary
High-mobility group box 1 (HMGB1) is a nucleoprotein that is related to inflammation It has been implicated in a variety of biologically important processes, including transcription, DNA repair, differentiation, development, and extracellular signaling. HMGB1 promotes inflammation by binding to the receptors, such as the receptor for advanced glycation end-products (RAGE), Toll-like receptor (TLR) 2, and TLR-4, which are expressed in a variety of cells including monocytes, macrophages, and endothelial cells [7,9,10,11,12]. Increased RAGE-HMGB1 activity induces phosphorylation of extracellular signal-related kinase (ERK) [28], activating GTPases of the Rho family [29] It contributes to cancer development through different mechanisms, including angiogenesis [28], cell migration [30], and apoptosis inhibition [24]. The role of HMGB1 in cancer development and progression, as well as its effect on the response to treatment, remains largely unexplored
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