Metabolic reprogramming is a cellular process contributing to carcinogenesis. However, it remains poorly understood in adrenal cortical carcinoma (ACC), an aggressive malignancy with overall poor prognosis and limited therapeutic options. We characterized the metabolic phenotype of ACC, by examining the immunoprofile of key proteins involved in glucose metabolism, hexokinase (HK1), pyruvate kinase (PKM1, PKM2), succinate dehydrogenase (SDHB), and phospho-S6 ribosomal protein (pS6), in a tissue microarray of 137 adrenal cortical tissue samples. Protein expression was compared between ACC (n = 42), adrenal cortical adenoma (ACA; n = 50), and normal adrenal cortical tissue samples (n = 45). Cytoplasmic expression of HK1 and PKM2 was significantly higher in ACC than in ACA (p < 0.001 and p = 0.014, respectively) or normal adrenal cortical tissue samples (p < 0.001 and p < 0.001, respectively). Expression of HK1 and PKM2 was also higher in ACA than in normal adrenal cortical tissue samples (p < 0.001 and p < 0.001, respectively). PKM1 expression was overall low in ACC, ACA, and normal samples, although expression of PKM1 was higher in ACC than in ACA (p = 0.027). There was no loss of cytoplasmic granular SDHB expression in our cohort of adrenal cortical tumors, and cytoplasmic expression of pS6 was lower in ACC than in ACA (p = 0.003) or normal adrenal cortical tissue samples (p = 0.008). Significantly, HK1 expression correlated with pyruvate kinase isoform (PKM2 and PKM1) expression (p < 0.001 and p = 0.007, respectively). Although functional validation was not performed, this study provides further evidence that metabolic reprogramming and altered glucose metabolism may occur in a subset of ACC through overexpression of intracellular glycolytic enzymes, notably HK1 and PKM2. The possibility of utilizing the reprogrammed glucose metabolism in ACC for novel therapeutic strategies should be explored in future studies.

中文翻译：

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肾上腺皮质癌代谢表型的免疫组织化学分析。

代谢重编程是导致癌变的细胞过程。然而，在肾上腺皮质癌（ACC），侵袭性恶性肿瘤，总体预后不良和治疗选择有限的情况下，对它的了解仍然很少。我们通过检查参与葡萄糖代谢的关键蛋白，己糖激酶（HK1），丙酮酸激酶（PKM1，PKM2），琥珀酸脱氢酶（SDHB）和磷酸S6核糖体蛋白（pS6）的免疫特征来表征ACC的代谢表型。 137个肾上腺皮质组织样本的组织芯片。比较了ACC（n  = 42），肾上腺皮质腺瘤（ACA; n  = 50）和正常肾上腺皮质组织样品（n = 45）。HK1和PKM2在ACC中的细胞质表达显着高于ACA（分别为p  <0.001和p  = 0.014）或正常肾上腺皮质组织样品（分别为p  <0.001和p  <0.001）。ACA中HK1和PKM2的表达也高于正常肾上腺皮质组织样品（分别为p  <0.001和p  <0.001）。尽管ACC中PKM1的表达高于ACA（p  = 0.027），但ACC，ACA和正常样品中PKM1的表达总体较低。在我们的肾上腺皮质肿瘤队列中，细胞质颗粒状SDHB表达没有损失，并且在ACC中pS6的细胞质表达低于ACA（p  = 0.003）或正常的肾上腺皮质组织样本（p  = 0.008）。明显地，HK1表达与丙酮酸激酶同工型（PKM2和PKM1）表达相关（分别为p  ＜0.001和p  ＝ 0.007）。尽管未进行功能验证，但这项研究提供了进一步的证据，表明通过细胞内糖酵解酶（尤其是HK1和PKM2）的过表达，在ACC的一个子集中可能发生代谢重编程和葡萄糖代谢改变。在未来的研究中应探讨在ACC中利用重新编程的葡萄糖代谢进行新的治疗策略的可能性。