Germline-specific genes are usually activated in cancer cells and drive cancer progression; such genes are called cancer-germline or cancer-testis genes. The RNA-binding protein DAZL is predominantly expressed in germ cells and plays a role in gametogenesis as a translational activator or repressor. However, its expression and role in non-small cell lung cancer (NSCLC) are unknown. Here, mining of RNA-sequencing data from public resources and immunohistochemical analysis of tissue microarrays showed that DAZL was expressed exclusively in testis among normal human tissues but ectopically expressed in NSCLC tissues. Testis and NSCLC cells expressed the shorter and longer transcript variants of the DAZL gene, respectively. Overexpression of the longer DAZL transcript promoted tumor growth in a mouse xenograft model. Silencing of DAZL suppressed cell proliferation, colony formation, migration, invasion, and cisplatin resistance in vitro and tumor growth in vivo. Quantitative proteomic analysis based on tandem mass tag and Western blot analysis showed that DAZL upregulated the expression of JAK2 and MCM8. RNA-binding protein immunoprecipitation assays showed that DAZL bound to the mRNA of JAK2 and MCM8. The JAK2 inhibitor fedratinib attenuated the oncogenic outcomes induced by DAZL overexpression, whereas silencing MCM8 counteracted the effects of DAZL overexpression on cisplatin-damaged DNA synthesis and half-maximal inhibitory concentration of cisplatin. In conclusion, DAZL was identified as a novel cancer-germline gene that enhances the translation of JAK2 and MCM8 to promote NSCLC progression and resistance to cisplatin, respectively. These findings suggest that DAZL is a potential therapeutic target in NSCLC.

中文翻译：

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一种新型癌症种系基因 DAZL 通过上调 JAK2 和 MCM8 促进非小细胞肺癌的进展和顺铂耐药

种系特异性基因通常在癌细胞中被激活并驱动癌症进展；这些基因被称为癌症种系基因或癌症睾丸基因。 RNA 结合蛋白 DAZL 主要在生殖细胞中表达，并作为翻译激活剂或阻遏物在配子发生中发挥作用。然而，其在非小细胞肺癌（NSCLC）中的表达和作用尚不清楚。在这里，从公共资源中挖掘RNA测序数据和组织微阵列的免疫组织化学分析表明，DAZL在正常人体组织中仅在睾丸中表达，但在NSCLC组织中异位表达。睾丸和 NSCLC 细胞分别表达 DAZL 基因的较短和较长的转录变体。较长 DAZL 转录物的过度表达促进了小鼠异种移植模型中的肿瘤生长。沉默 DAZL 可抑制体外细胞增殖、集落形成、迁移、侵袭和顺铂耐药性以及体内肿瘤生长。基于串联质量标签和蛋白质印迹分析的定量蛋白质组分析表明，DAZL 上调 JAK2 和 MCM8 的表达。 RNA 结合蛋白免疫沉淀测定表明 DAZL 与 JAK2 和 MCM8 的 mRNA 结合。 JAK2抑制剂fedratinib减弱了DAZL过度表达诱导的致癌结果，而沉默MCM8则抵消了DAZL过度表达对顺铂损伤的DNA合成和顺铂半最大抑制浓度的影响。总之，DAZL 被确定为一种新型癌症种系基因，可增强 JAK2 和 MCM8 的翻译，分别促进 NSCLC 进展和顺铂耐药。这些发现表明 DAZL 是 NSCLC 的潜在治疗靶点。