FAM46C is a well-established tumour suppressor with a role that is not completely defined or universally accepted. Although FAM46C expression is down-modulated in several tumours, significant mutations in theFAM46Cgene are only found in multiple myeloma (MM). Consequently, its tumour suppressor activity has primarily been studied in the MM context. However, emerging evidence suggests that FAM46C is involved also in other cancer types, namely colorectal, prostate and gastric cancer and squamous cell and hepatocellular carcinoma, where FAM46C expression was found to be significantly reduced in tumoural versus non-tumoural tissues and where FAM46C was shown to possess anti-proliferative properties. Accordingly, FAM46C was recently proposed to function as a pan-cancer prognostic marker, bringing FAM46C under the spotlight and attracting growing interest from the scientific community in the pathways modulated by FAM46C and in its mechanistic activity. Here, we will provide the first comprehensive review regarding FAM46C by covering (1) the intracellular pathways regulated by FAM46C, namely the MAPK/ERK, PI3K/AKT, β-catenin and TGF-β/SMAD pathways; (2) the models regarding its mode of action, specifically the poly(A) polymerase, intracellular trafficking modulator and inhibitor of centriole duplication models, focusing on connections and interdependencies; (3) the regulation of FAM46C expression in different environments by interferons, IL-4, TLR engagement or transcriptional modulators; and, lastly, (4) how FAM46C expression levels associate with increased/decreased tumour cell sensitivity to anticancer agents, such as bortezomib, dexamethasone, lenalidomide, pomalidomide, doxorubicin, melphalan, SK1-I, docetaxel and norcantharidin.
FAM46C是一种已被确认的肿瘤抑制因子，但其具体作用机制尚未完全明确且存在学术争议。尽管FAM46C在多种肿瘤中表达下调，但该基因的显著突变仅见于多发性骨髓瘤。因此，其抑癌功能的研究主要集中于多发性骨髓瘤领域。然而，最新证据表明FAM46C也参与结直肠癌、前列腺癌、胃癌、鳞状细胞癌及肝细胞癌等恶性肿瘤的发展进程——在这些癌种中，肿瘤组织的FAM46C表达量较非肿瘤组织显著降低，且被证实具有抑制细胞增殖的特性。基于此，近期研究提出FAM46C可能作为泛癌种预后标志物，这使其成为研究热点，科学界对其调控通路及作用机制的关注度持续攀升。本文首次对FAM46C进行系统性综述，涵盖以下四个维度：（1）FAM46C调控的细胞内通路，包括MAPK/ERK、PI3K/AKT、β-catenin及TGF-β/SMAD信号通路；（2）其作用机制模型，重点阐释多聚腺苷酸聚合酶模型、细胞内运输调节模型及中心粒复制抑制模型之间的关联性与依存关系；（3）干扰素、IL-4、Toll样受体激活及转录调节因子在不同微环境中对FAM46C表达的调控机制；（4）FAM46C表达水平如何影响肿瘤细胞对硼替佐米、地塞米松、来那度胺、泊马度胺、多柔比星、美法仑、SK1-I、多西他赛及去甲斑蝥素等抗癌药物的敏感性变化。
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