Department of Pathology, MedStar Georgetown University Hospital, 20007, Washington, DC, USA.
Department of Biology, The Catholic University of America, 620 Michigan Avenue, NE, 103 McCort-Ward, 20064, Washington, DC, USA.
Sci Rep. 2024 Oct 18;14(1):24488. doi: 10.1038/s41598-024-75219-1.
Genomic instability is associated with late stage carcinomas and the epithelial mesenchymal transition (EMT). Of note is chromosome 8q24 amplification that has been documented in many epithelial-derived carcinomas. On this amplified region is the potent oncogene, c-myc. Not only does MYC overexpression activate targets that promote cell proliferation, it also activates transcription factors that drive EMT, including ZEB1. Further reinforcing EMT, overexpressed MYC also represses tumor suppressors involved in promoting the epithelial phenotype, including MIZ1. We predict that as carcinomas progress, chromosome 8q24 is amplified leading to high MYC levels that leads to ZEB1 expression and MIZ1 repression driving cells through EMT. To interrogate this clinically, limited cohorts of human epithelial-derived carcinomas were examined for MYC/ZEB1/MIZ1 expression patterns across increasing carcinoma grades. Interestingly, the predicted temporal patterns were only observed in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinomas. Yet MIZ1 proved to be an excellent marker to assess carcinoma progression across types. We expanded the HCC cohort and determined that c-myc amplification was restricted to grade III/IV HCC that also exhibited increased MYC and ZEB1 nuclear expression whereas cytosolic MIZ1 expression was lost and only nuclear expression retained. These same resections were obtained from only individuals who had histories of alcohol consumption that were also diagnosed with cirrhosis, metastasis and had viral hepatitis suggesting etiology-specific mechanisms of cancer progression. Finally, analysis performed in Hep3B cells determined that alterations in MYC expression promoted the predicted changes in ZEB1 and MIZ1 expression and/or distributions and in markers for EMT further suggesting a relationship among these three transcription factors in HCC and their correlation to driving EMT.
基因组不稳定性与晚期癌和上皮间质转化（EMT）有关。值得注意的是，许多上皮源性癌中都有染色体 8q24 扩增。在这个扩增区域是强有力的癌基因 c-myc。不仅 MYC 过表达激活了促进细胞增殖的靶标，还激活了驱动 EMT 的转录因子，包括 ZEB1。进一步强化 EMT，过表达的 MYC 还抑制了参与促进上皮表型的肿瘤抑制因子，包括 MIZ1。我们预测，随着癌的进展，染色体 8q24 扩增导致高水平的 MYC，导致 ZEB1 表达和 MIZ1 抑制，从而驱动细胞通过 EMT。为了在临床上研究这一点，我们对有限的人类上皮源性癌队列进行了研究，以检查 MYC/ZEB1/MIZ1 的表达模式在癌分级增加的过程中。有趣的是，只有在肝细胞癌（HCC）和肝内胆管细胞癌中观察到预测的时间模式。然而，MIZ1 被证明是评估跨类型癌进展的优秀标志物。我们扩大了 HCC 队列，并确定 c-myc 扩增仅限于 III/IV 级 HCC，这些 HCC 还表现出 MYC 和 ZEB1 核表达增加，而细胞质 MIZ1 表达丢失，仅保留核表达。这些相同的切除仅从那些有饮酒史的个体中获得，这些个体也被诊断为肝硬化、转移和病毒性肝炎，这表明癌症进展的病因特异性机制。最后，在 Hep3B 细胞中的分析表明，MYC 表达的改变促进了 ZEB1 和 MIZ1 表达和/或分布的预测变化，以及 EMT 的标志物，进一步表明在 HCC 中这三个转录因子之间存在关系，以及它们与 EMT 驱动的相关性。
