Department of Otolaryngology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan, Republic of China.
Institutes of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan, Republic of China.
Cell Oncol (Dordr). 2022 Oct;45(5):893-909. doi: 10.1007/s13402-022-00695-4. Epub 2022 Aug 5.
Although YAP1 and TAZ are believed to be equivalent downstream effectors of the Hippo pathway, differential expression of YAP1 or TAZ suggests distinct functions during cancer progression. The exact role of YAP1 and TAZ in esophageal cancer, the 6th leading cancer-related mortality in the world, remains elusive.
Following single or double manipulation of YAP1 or TAZ expression, we subjected these manipulated cells to proliferation, migration, invasion, and xenograft tumorigenesis assays. We used RT-qPCR and Western blotting to examine their expression in the manipulated cells with or without inhibition of transcription or translation. We also examined the impact of YAP1 or TAZ deregulation on clinical outcome of esophageal cancer patients from the TCGA database.
We found that YAP1 functions as a tumor suppressor whereas TAZ exerts pro-tumor functions in esophageal cancer cells. We also found a significant increase in TAZ mRNA expression upon YAP1 depletion, but not vice versa, despite the downregulation of CTGF and CYR61, shared targets of YAP1 and TAZ, in xenografted tissue cells. In addition to transcriptional regulation, YAP1-mediated TAZ expression was found to occur via protein synthesis. Restored TAZ expression mitigated YAP1-mediated suppression of cellular behavior. By contrast, TAZ silencing reduced the promoting effect exerted by YAP1 depletion on cellular behaviors. The observed anti-tumor function of YAP1 was further supported by a better overall survival among esophageal cancer patients with a high YAP1 expression.
From our data we conclude that YAP1 functions as a suppressor and negatively regulates pro-tumor TAZ expression via transcriptional and translational control in esophageal cancer.
虽然 YAP1 和 TAZ 被认为是 Hippo 通路的等效下游效应物，但 YAP1 或 TAZ 的差异表达表明它们在癌症进展过程中具有不同的功能。YAP1 和 TAZ 在食管癌中的确切作用（世界上第六大与癌症相关的死亡原因）仍不清楚。
在单独或双重操纵 YAP1 或 TAZ 的表达后，我们将这些操纵的细胞进行增殖、迁移、侵袭和异种移植肿瘤发生测定。我们使用 RT-qPCR 和 Western blot 来检测转录或翻译抑制时这些操纵细胞中的表达。我们还从 TCGA 数据库中检查了 YAP1 或 TAZ 失调对食管癌患者临床结果的影响。
我们发现 YAP1 在食管癌细胞中作为肿瘤抑制因子发挥作用，而 TAZ 则发挥促肿瘤作用。我们还发现，尽管 CTGF 和 CYR61（YAP1 和 TAZ 的共同靶标）下调，但在异种移植组织细胞中，YAP1 耗竭后 TAZ mRNA 表达显著增加，而不是相反。除了转录调控外，还发现 YAP1 介导的 TAZ 表达是通过蛋白质合成发生的。恢复的 TAZ 表达减轻了 YAP1 介导的对细胞行为的抑制作用。相比之下，TAZ 沉默减少了 YAP1 耗竭对细胞行为的促进作用。YAP1 的观察到的抗肿瘤功能进一步得到了具有高 YAP1 表达的食管癌患者总体生存率提高的支持。
根据我们的数据，我们得出结论，YAP1 在食管癌中作为抑制物发挥作用，并通过转录和翻译控制负调控促肿瘤 TAZ 表达。
