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The antioxidant transcription factor Nrf2 modulates the stress response and phenotype of malignant as well as premalignant pancreatic ductal epithelial cells by inducing expression of the ATF3 splicing variant ΔZip2.
Oncogene ( IF 6.9 ) Pub Date : 2018-Oct-09 , DOI: 10.1038/s41388-018-0518-3
My-Lan Kha , Lisa Hesse , Florian Deisinger , Bence Sipos , Christoph Röcken , Alexander Arlt , Susanne Sebens , Ole Helm , Heiner Schäfer

Pancreatic ductal adenocarcinoma (PDAC) exhibits one of the worst survival rates of all cancers. While death rates show declining trends in the majority of cancers, PDAC registers rising rates. Based on the recently described crosstalk between TGF-β1 and Nrf2 in the PDAC development, the involvement of ATF3 and its splice variant ΔZip2 in TGF-β1- and Nrf2-driven pancreatic tumorigenesis was investigated. As demonstrated here, PDAC (Panc1, T3M4) cells or premalignant H6c7 pancreatic ductal epithelial cells differentially express ΔZip2- and ATF3, relating to stronger Nrf2 activity seen in Panc1 cells and TGF-ß1 activity in T3M4 or H6c7 cells, respectively. Treatment with the electrophile/oxidative stress inducer tBHQ or the cytostatic drug gemcitabine strongly elevated ΔZip2 expression in a Nrf2-dependent fashion. The differential expression of ATF3 and ΔZip2 in response to Nrf2 and TGF-ß1 relates to differential ATF3-gene promoter usage, giving rise of distinct splice variants. Nrf2-dependent ΔZip2 expression confers resistance against gemcitabine-induced apoptosis, only partially relating to interference with ATF3 and its proapoptotic activity, e.g., through CHOP-expression. In fact, ΔZip2 autonomously activates expression of cIAP anti-apoptotic proteins. Moreover, ΔZip2 favors and ATF3 suppresses growth and clonal expansion of PDAC cells, again partially independent of each other. Using a Panc1 tumor xenograft model in SCID-beige mice, the opposite activities of ATF3 and ΔZip2 on tumor-growth and chemoresistance were verified in vivo. Immunohistochemical analyses confirmed ΔZip2 and Nrf2 coexpression in cancerous and PanIN structures of human PDAC and chronic pancreatitis tissues, respectively, which to some extent was reciprocal to ATF3 expression. It is concluded that depending on selective ATF3-gene promoter usage by Nrf2, the ΔZip2 expression is induced in response to electrophile/oxidative (here through tBHQ) and xenobiotic (here through gemcitabine) stress, providing apoptosis protection and growth advantages to pancreatic ductal epithelial cells. This condition may substantially add to pancreatic carcinogenesis driven by chronic inflammation.

中文翻译:

抗氧化剂转录因子Nrf2通过诱导ATF3剪接变体ΔZip2的表达来调节恶性和恶变前胰腺导管上皮细胞的应激反应和表型。

胰腺导管腺癌(PDAC)表现出所有癌症中最差的生存率之一。虽然死亡率在大多数癌症中呈下降趋势,但PDAC的死亡率却在上升。基于最近描述的PDAC发育中TGF-β1和Nrf2之间的串扰,研究了ATF3及其剪接变体ΔZip2在TGF-β1和Nrf2驱动的胰腺肿瘤发生中的作用。如此处所示,PDAC(Panc1,T3M4)细胞或癌前H6c7胰腺导管上皮细胞差异表达ΔZip2-和ATF3,分别与Panc1细胞中的Nrf2活性和T3M4或H6c7细胞中的TGF-ß1活性有关。用亲电试剂/氧化应激诱导剂tBHQ或抑制细胞生长的药物吉西他滨以Nrf2依赖性方式显着提高ΔZip2表达。响应Nrf2和TGF-ß1的ATF3和ΔZip2的差异表达与ATF3基因启动子的差异使用有关,产生了不同的剪接变体。Nrf2依赖的ΔZip2表达赋予了对吉西他滨诱导的细胞凋亡的抗性,仅部分与干扰ATF3及其促凋亡活性有关,例如通过CHOP表达。实际上,ΔZip2自主激活cIAP抗凋亡蛋白的表达。此外,ΔZip2有利于ATF3抑制PDAC细胞的生长和克隆扩增,它们又部分彼此独立。使用SCID-beige小鼠的Panc1肿瘤异种移植模型,在体内验证了ATF3和ΔZip2对肿瘤生长和化学抗性的相反活性。免疫组织化学分析分别证实了人PDAC和慢性胰腺炎组织的癌性和PanIN结构中的ΔZip2和Nrf2共表达,在某种程度上与ATF3表达呈正相关。结论是,取决于Nrf2选择性使用ATF3-基因启动子,ΔZip2表达是响应亲电/氧化(通过tBHQ)和异种生物(通过吉西他滨)胁迫而诱导的,为胰腺导管上皮细胞提供了凋亡保护和生长优势细胞。这种情况可能会大大增加由慢性炎症驱动的胰腺癌的发生。响应亲电/氧化(此处通过tBHQ)和异种生物(此处通过吉西他滨)胁迫诱导ΔZip2表达,为胰腺导管上皮细胞提供凋亡保护和生长优势。这种情况可能会大大增加由慢性炎症驱动的胰腺癌的发生。响应亲电/氧化(此处通过tBHQ)和异种生物(此处通过吉西他滨)胁迫诱导ΔZip2表达,为胰腺导管上皮细胞提供凋亡保护和生长优势。这种情况可能会大大增加由慢性炎症驱动的胰腺癌的发生。
更新日期:2018-10-10
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