两篇癌研究论文:影响肿瘤转移的原癌基因
生物通 · 2017/02/10
停留在原地的癌症并不可怕,癌症造成死亡大多是因为疾病扩散到了重要的器官,这一过程被称为癌转移。近期来自同济大学和厦门大学的两组研究人员分别通过研究,发现了两种原癌基因对肿瘤转移的不同作用:第一项研究发现原癌基因Myc不仅能够抑制肿瘤浸润,还能调控正常发育中的细胞迁移;第二项研究指出原癌基因c-Src能通过磷酸化糖酵解中的限速酶己糖激酶(hexokinase, HK)增加其活性,进而促进肿瘤发生和转移的机理。


停留在原地的癌症并不可怕,癌症造成死亡大多是因为疾病扩散到了重要的器官,这一过程被称为癌转移。近期来自同济大学和厦门大学的两组研究人员分别通过研究,发现了两种原癌基因对肿瘤转移的不同作用:第一项研究发现原癌基因Myc不仅能够抑制肿瘤浸润,还能调控正常发育中的细胞迁移;第二项研究指出原癌基因c-Src能通过磷酸化糖酵解中的限速酶己糖激酶(hexokinase, HK)增加其活性,进而促进肿瘤发生和转移的机理。

这两项成果分别公布在Oncogene和Nature Communications杂志上。

肿瘤迁移是癌症致死的主要原因,探明肿瘤迁移的分子机制是预防和治疗癌症的关键。Myc是一个重要的原癌基因,在大多数人类癌症中表达量升高,并与肿瘤的发生密切相关,但其在肿瘤细胞侵袭和迁移中的作用仍存在很大争议。

同济大学的研究人员利用果蝇建立了肿瘤迁移的动物模型,并以此开展大规模的遗传筛选,发现Myc不仅能够抑制肿瘤浸润,还能调控正常发育中的细胞迁移。研究发现Myc和Max形成二聚体,作为转录因子结合在puc基因的调控区,激活puc的表达,从而抑制JNK信号通路介导的细胞迁移和肿瘤浸润。在果蝇中表达人类同源基因cMyc,也能有效的抑制细胞迁移和肿瘤浸润,证明Myc的这项功能在进化中高度保守。此外,研究人员在体外培养的人类肺癌细胞PC9中进一步证实,过表达cMyc能下调JNK信号通路并减缓肺癌细胞的迁移;反之,敲低cMyc则上调JNK信号通路并促进肿瘤细胞的迁移。

这项研究不仅揭示了Myc对细胞迁移和肿瘤浸润的调控机制,也为Myc相关癌症的治疗提供了理论依据。

另外一项研究发现c-Src在激活的情况下能够和HK相互结合,并且磷酸化Ⅰ型己糖激酶(HK1)的酪氨酸732位点以及Ⅱ型己糖激酶(HK2)的酪氨酸686位点。磷酸化修饰导致HK构象的改变,增强其对葡萄糖的亲和力,进而激活其催化活性。激活的HK使大量的葡萄糖被摄入转化为6-磷酸葡萄糖,促进糖酵解。深入的研究表明c-Src磷酸化HK能够促进肿瘤的形成和转移。在临床结肠癌和肺癌中HK1-Y732的磷酸化水平显著升高,且在转移瘤中高于原发瘤,说明检测该位点的磷酸化对相关肿瘤的治疗和预后评估有一定的借鉴作用。

这一研究不仅揭示了c-Src促进肿瘤的发生和转移的新机理,而且为相关肿瘤的治疗和预后评估提供了理论依据。

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  • Myc suppresses tumor invasion and cell migration by inhibiting JNK signaling

    Tumor metastasis, but not primary overgrowth, is the leading cause of mortality for cancer patients. During the past decade, Drosophila melanogaster has been well-accepted as an excellent model to address the intrinsic mechanism of different aspects of cancer progression, ranging from tumor initiation to metastasis. In a genetic screen performed in Drosophila, aiming to find novel modulators of tumor invasion, we identified the oncoprotein Myc as a negative regulator. While expression of Myc dramatically blocks tumor invasion and cell migration, loss of Myc promotes cell migration in vivo. The activity of Myc is further enhanced by the co-expression of its transcription partner Max. Mechanistically, we found Myc/Max directly upregulates the transcription of puc, which encodes an inhibitor of JNK signaling crucial for tumor invasion and cell migration. Furthermore, we demonstrated that human cMyc potently suppresses JNK-dependent cell invasion and migration in both Drosophila and lung adenocarcinoma cell lines. These findings provide novel molecular insights into Myc-mediated cancer progression and raise the noteworthy problem in therapeutic strategies as inhibiting Myc might conversely accelerate tumor metastasis.

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  • c-Src phosphorylation and activation of hexokinase promotes tumorigenesis and metastasis

    It is well known that c-Src has important roles in tumorigenesis. However, it remains unclear whether c-Src contributes to metabolic reprogramming. Here we find that c-Src can interact with and phosphorylate hexokinases HK1 and HK2, the rate-limiting enzymes in glycolysis. Tyrosine phosphorylation dramatically increases their catalytic activity and thus enhances glycolysis. Mechanistically, c-Src phosphorylation of HK1 at Tyr732 robustly decreases its Km and increases its Vmax by disrupting its dimer formation. Mutation in c-Src phosphorylation site of either HK1 or HK2 remarkably abrogates the stimulating effects of c-Src on glycolysis, cell proliferation, migration, invasion, tumorigenesis and metastasis. Due to its lower Km for glucose, HK1 rather than HK2 is required for tumour cell survival when glucose is scarce. Importantly, HK1-Y732 phosphorylation level remarkably correlates with the incidence and metastasis of various clinical cancers and may serve as a marker to predict metastasis risk of primary cancers.

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