Background & Aims

The Fragile X Mental Retardation Protein (FMRP) affects multiple steps of the mRNA metabolism during brain development and in different neoplastic processes. However, the contribution of FMRP in colon carcinogenesis has not been investigated.

Methods

FMRP transcripts and proteins expression were analyzed in human colon samples derived from patients with sporadic CRC and healthy subjects. We used a well-established mouse model of sporadic CRC induced by Azoxymethane (AOM) to determine the possible role of FMRP in CRC. To address whether FMRP controls cancer cell survival, we analyzed cell death pathway in CRC human epithelial cell lines and in patient-derived colon cancer organoid in presence or absence of a specific FMRP antisense oligonucleotide or siRNA.

Results

We document a significant increase of FMRP in human CRC relative to non-tumor tissues. Next, using an inducible mouse model of CRC, we observed a reduction of colonic tumor incidence and size in the Fmr1 KO mice. The abrogation of FMRP induced spontaneous cell death in human CRC cells lines activating the necroptotic pathway. Indeed, specific immunoprecipitation experiments on human cell lines and CRC samples indicate that FMRP binds receptor-interacting protein kinase 1 (RIPK1) mRNA suggesting that FMRP acts as a master regulator of necroptosis pathway through the surveillance of RIPK1 mRNA metabolism. Treatment of human CRC cells lines and patient-derived colon cancer organoids with the FMR1 antisense results in an upregulation of RIPK1, which drives the CRC human cell towards the necroptosis.

Conclusions

Altogether, these data support a role for FMRP in sustaining colon tumorigenesis controlling the RIPK1 expression and ultimately abrogating the activation of the necroptotic pathway.

中文翻译：

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Fragile X Mental Retardation Protein 调节 RIP1K 和结直肠癌对坏死性凋亡的抵抗

背景与目标

脆性 X 智力迟钝蛋白 (FMRP) 影响大脑发育和不同肿瘤过程中 mRNA 代谢的多个步骤。然而，尚未研究 FMRP 在结肠癌发生中的作用。

方法

在来自散发性 CRC 患者和健康受试者的人类结肠样本中分析了 FMRP 转录物和蛋白质表达。我们使用由偶氮甲烷 (AOM) 诱导的散发性 CRC 的完善小鼠模型来确定 FMRP 在 CRC 中的可能作用。为了解决 FMRP 是否控制癌细胞存活，我们在存在或不存在特定 FMRP 反义寡核苷酸或 siRNA 的情况下分析了 CRC 人上皮细胞系和患者来源的结肠癌类器官中的细胞死亡途径。

结果

我们记录了人类 CRC 中 FMRP 相对于非肿瘤组织的显着增加。接下来，使用可诱导的 CRC 小鼠模型，我们观察到Fmr1 KO 小鼠结肠肿瘤发生率和大小的降低。FMRP 的废除在激活坏死性凋亡途径的人 CRC 细胞系中诱导自发性细胞死亡。事实上，对人类细胞系和 CRC 样本的特定免疫沉淀实验表明 FMRP 结合受体相互作用蛋白激酶 1 ( RIPK1 ) mRNA，这表明 FMRP 通过监视RIPK1 mRNA 代谢充当坏死性凋亡途径的主要调节剂。用FMR1治疗人 CRC 细胞系和患者来源的结肠癌类器官 反义导致 RIPK1 的上调，这会促使 CRC 人类细胞发生坏死性凋亡。

结论

总而言之，这些数据支持 FMRP 在维持结肠肿瘤发生中的作用，控制 RIPK1 表达并最终取消坏死性途径的激活。