Loss of RNF43 Function Contributes to Gastric Carcinogenesis by Impairing DNA Damage Response,Cellular and Molecular Gastroenterology and Hepatology

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Loss of RNF43 Function Contributes to Gastric Carcinogenesis by Impairing DNA Damage Response
Cellular and Molecular Gastroenterology and Hepatology ( IF 7.1 ) Pub Date : 2020-11-11 , DOI: 10.1016/j.jcmgh.2020.11.005
Victoria Neumeyer ₁ , Anna Brutau-Abia ₁ , Michael Allgäuer ₁ , Nicole Pfarr ₂ , Wilko Weichert ₂ , Christina Falkeis-Veits ₃ , Elisabeth Kremmer ₄ , Michael Vieth ₃ , Markus Gerhard ₁ , Raquel Mejías-Luque ₁

Affiliation

Background & Aims

RING finger protein 43 (RNF43) is a tumor suppressor that frequently is mutated in gastric tumors. The link between RNF43 and modulation of Wingless-related integration site (WNT) signaling has not been shown clearly in the stomach. Because mutations in RNF43 are highly enriched in microsatellite-unstable gastric tumors, which show defects in DNA damage response (DDR), we investigated whether RNF43 is involved in DDR in the stomach.

Methods

DDR activation and cell viability upon γ-radiation was analyzed in gastric cells where expression of RNF43 was depleted. Response to chemotherapeutic agents 5-fluorouracil and cisplatin was analyzed in gastric cancer cell lines and xenograft tumors. In addition, involvement of RNF43 in DDR activation was analyzed upon Helicobacter pylori infection in wild-type and Rnf43^ΔEx8 mice. Furthermore, a cohort of human gastric biopsy specimens was analyzed for RNF43 expression and mutation status as well as for activation of DDR.

Results

RNF43 depletion conferred resistance to γ-radiation and chemotherapy by dampening the activation of DDR, thereby preventing apoptosis in gastric cells. Upon Helicobacter pylori infection, RNF43 loss of function reduced activation of DDR and apoptosis. Furthermore, RNF43 expression correlated with DDR activation in human gastric biopsy specimens, and RNF43 mutations found in gastric tumors conferred resistance to DNA damage. When exploring the molecular mechanisms behind these findings, a direct interaction between RNF43 and phosphorylated H2A histone family member X (γH2AX) was observed.

Conclusions

We identified a novel function for RNF43 in the stomach as a regulator of DDR. Loss of RNF43 function in gastric cells confers resistance to DNA damage-inducing radiotherapy and chemotherapy, suggesting RNF43 as a possible biomarker for therapy selection.

中文翻译：

RNF43 功能的丧失通过损害 DNA 损伤反应导致胃癌发生

背景与目标

环指蛋白 43 (RNF43) 是一种肿瘤抑制因子，在胃肿瘤中经常发生突变。RNF43 与 Wingless 相关整合位点 (WNT) 信号调制之间的联系尚未在胃中清楚地显示出来。因为RNF43的突变在微卫星不稳定的胃肿瘤中高度富集，显示出 DNA 损伤反应 (DDR) 的缺陷，我们研究了 RNF43 是否参与胃中的 DDR。

方法

在 RNF43 表达被耗尽的胃细胞中分析了 γ 辐射后的 DDR 活化和细胞活力。在胃癌细胞系和异种移植肿瘤中分析了对化疗药物 5-氟尿嘧啶和顺铂的反应。此外，在野生型和Rnf43 ^ΔEx8小鼠感染幽门螺杆菌后，分析了 RNF43 参与 DDR 激活。此外，分析了一组人胃活检标本的 RNF43 表达和突变状态以及 DDR 的激活。

结果

RNF43 耗竭通过抑制 DDR 的活化赋予对 γ 辐射和化学疗法的抗性，从而防止胃细胞凋亡。在幽门螺杆菌感染后，RNF43 功能丧失减少了 DDR 的激活和细胞凋亡。此外，RNF43 表达与人胃活检标本中的 DDR 激活相关，胃肿瘤中发现的RNF43突变赋予了对 DNA 损伤的抵抗力。在探索这些发现背后的分子机制时，观察到 RNF43 和磷酸化 H2A 组蛋白家族成员 X (γH2AX) 之间的直接相互作用。