Abstract
ObjectiveWe previously reported the identification of monocarboxylate transporter 4 (MCT4) and glypican-3 (GPC3) as prognostic factors for hepatocellular carcinoma (HCC), which are now considered significant poor prognostic factors for the disease. This study aimed to clarify the detailed interaction of these two factors in HCC to improve our understanding of aggressive HCC phenotypes. A total of 225 Japanese patients with HCC from our previous study were subjected to immunohistochemical analyses.ResultsThe number of MCT4-positive (MCT4+) HCC cases was 47 (21%), and most MCT4+ HCC showed high GPC3 expression (94%, 44/47 cases). In 44 MCT4+/GPC3+ HCC cases, intratumoral heterogeneity of GPC3 or MCT4 expression was further evaluated. We observed reciprocal (inverse), synergistic, mixed reciprocal and synergistic, or irrelevant interaction of MCT4 and GPC3 expression in 29 (66%), 5 (11%), 1 (2%), and 9 cases (21%), respectively. The cases exhibiting reciprocal expression of both markers tended to have cirrhosis without a history of neoadjuvant therapy. In summary, although MCT4+ HCC cases are mostly GPC3+, intratumoral expression patterns of MCT4 and GPC3 are frequently reciprocal each other, suggesting that dual targeting of MCT4 and GPC3 may achieve a better antitumor effect for MCT4+ HCC cases.
Highlights
Liver cancer is the leading cause of cancer death worldwide and is the second leading cause of cancer death in men [1]
We previously reported the identification of prognostic factors for hepatocellular carcinoma (HCC), including glypican-3 (GPC3) [2, 3] and monocarboxylate transporter 4 (MCT4) [4]
We previously reported that MCT4+ HCC cases were mostly GPC3 positive [4], and in the double-positive cases, MCT4+ HCC cells may show circumferential membranous GPC3 immunoreactivity [4]; this trend of synergistic immunoreactivity in the double-positive HCC was less pronounced in subsequent detailed examination using serial sections of each case
Summary
MCT4+ HCC and GPC3+ HCC were immunohistochemically identified in 21% (47 cases) and 84% (190 cases) of the 225 cases, respectively. Of the 44 MCT4+/GPC3+ HCC cases, we observed reciprocal, synergistic, reciprocal and synergistic, or irrelevant expression pattern of MCT4 and GPC3, which represented 66% (29 cases), 11% (5), 2% (1), and 21% (9) of the cases, respectively (Additional file 2). An intratumoral reciprocal (inverse) expression of MCT4 and GPC3 was the most frequent pattern in MCT4+/ GPC3+ HCCs, in which HCC cells with increased MCT4 showed decreased GPC3 immunoreactivity and vice versa (Fig. 1). Among 30 HCC cases having intratumoral reciprocal expression pattern of MCT4 and GPC3 (29 reciprocal cases and 1 mixed reciprocal and synergistic case), 22 showed the reciprocal pattern in > 50% of the MCT4-positive area. The reciprocal HCC cases were related to the existence of cirrhosis or absence of neoadjuvant therapy compared to the non-reciprocal HCC cases
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