Introduction: Hepatocellular carcinoma and hepatoblastoma are two liver cancers characterized by gene deregulations, chromosomal rearrangements, and mutations in Wnt/beta-catenin (Wnt) pathway-related genes. LHX2, a transcriptional factor member of the LIM homeobox gene family, has important functions in embryogenesis and liver development. LHX2 is oncogenic in many solid tumors and leukemia but its role in liver cancer is unknown. Methods: We analyzed the expression of LHX2 in hepatocellular carcinoma and hepatoblastoma samples using various transcriptomic datasets and biological samples. The role of LHX2 was studied using lentiviral transduction, in vitro cell-based assays (growth, migration, senescence, apoptosis), molecular approaches (phospho-kinase arrays, RNA-seq), bioinformatics and two in vivo models in chicken and Xenopus embryos. Results: We found a strong connection between LHX2 down-regulation and Wnt activation in these two liver cancers. In hepatoblastoma, LHX2 downregulation correlated with multiple poor outcome parameters including higher patient age, intermediate- and high-risk tumors and low patients’ survival. Forced expression of LHX2 reduced the proliferation, migration and survival of hepatoma cells in vitro through the inactivation of MAPK/ERK and Wnt signals. In vivo, LHX2 impeded the development of tumors in chick embryos and repressed the Wnt pathway in Xenopus embryos. RNA-sequencing data and bioinformatic analyses confirmed the deregulation of many biological functions and molecular processes associated with cell migration, cell survival and liver carcinogenesis in LHX2-expressing hepatoma cells. At a mechanistic level, LHX2 mediated the disassembling of beta-catenin/T-cell factor 4 complex and induced expression of multiple inhibitors of Wnt (e.g. TLE/Groucho) and MAPK/ERK (e.g. DUSPs) pathways. Conclusion: Collectively, our findings demonstrate a tumor suppressive function of LHX2 in adult and pediatric liver cancers.


中文翻译：

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LIM homeobox-2 通过灭活 MAPK/ERK 和 Wnt/β-连环蛋白通路抑制成人和儿童肝癌的特征

简介：肝细胞癌和肝母细胞瘤是两种肝癌，其特征是基因失调、染色体重排和 Wnt/β-连环蛋白 (Wnt) 通路相关基因的突变。LHX2 是 LIM 同源框基因家族的转录因子成员，在胚胎发生和肝脏发育中具有重要功能。LHX2 在许多实体瘤和白血病中具有致癌性，但其在肝癌中的作用尚不清楚。方法：我们使用各种转录组数据集和生物样本分析了肝细胞癌和肝母细胞瘤样本中 LHX2 的表达。使用慢病毒转导、基于体外细胞的测定（生长、迁移、衰老、凋亡）、分子方法（磷酸激酶阵列、RNA-seq）、生物信息学和鸡和爪蟾胚胎中的两个体内模型研究 LHX2 的作用. 结果：我们发现这两种肝癌中 LHX2 下调与 Wnt 激活之间存在密切联系。在肝母细胞瘤中，LHX2 下调与多个不良结果参数相关，包括较高的患者年龄、中危和高危肿瘤以及较低的患者生存率。LHX2 的强制表达通过 MAPK/ERK 和 Wnt 信号的失活降低了体外肝癌细胞的增殖、迁移和存活。在体内，LHX2 阻碍了鸡胚胎中肿瘤的发展，并抑制了爪蟾胚胎中的 Wnt 通路。RNA 测序数据和生物信息学分析证实，在表达 LHX2 的肝癌细胞中，与细胞迁移、细胞存活和肝癌发生相关的许多生物学功能和分子过程的失调。在机械层面，LHX2 介导β-连环蛋白/T 细胞因子4 复合物的分解并诱导多种Wnt（例如TLE/Groucho）和MAPK/ERK（例如DUSPs）通路抑制剂的表达。结论：总的来说，我们的研究结果表明 LHX2 在成人和儿童肝癌中具有抑癌功能。