導(dǎo)讀：

關(guān)于衰老與癌癥的因果關(guān)系,，最近的一篇nature文章給出了答案。

文章截圖

Abstract：

The risk of cancer and associated mortality increases substantially in humans from the age of 65 years onwards . Nonetheless, our understanding of the complex relationship between age and cancer is still in its infancy. For decades, this link has largely been attributed to increased exposure time to mutagens in older individuals. However, this view does not account for the established role of diet, exercise and small molecules that target the pace of metabolic ageing. Here we show that metabolic alterations that occur with age can produce a systemic environment that favours the progression and aggressiveness of tumours. Specifcally, we show that methylmalonic acid (MMA), a by-product of propionate metabolism, is upregulated in the serum of older people and functions as a mediator of tumour progression. We traced this to the ability of MMA to induce SOX4 expression and consequently to elicit transcriptional reprogramming that can endow cancer cells with aggressive properties. Thus, the accumulation of MMA represents a link between ageing and cancer progression, suggesting that MMA is a promising therapeutic target for advanced carcinomas.

原文摘要：

正文：    

     為了驗證這個猜想，他們分別用30名年輕(≤30歲)和30名老年(≥60歲)健康捐贈者的10%人血清(Human serum,，HS)培養(yǎng)了人類癌癥細胞（A549,、HCC1806）。

An age-induced circulatory factor promotes cancer aggression

年齡誘導(dǎo)的循環(huán)因子促進癌癥侵襲性

a, Diagram showing experimental design (see Methods). b, Immunoblots of A549 cells cultured for 4 days in HS from young or old donors; see Extended Data Fig. 4a (total of n = 30 biologically independent samples per HS donor group). c, Resistance to carboplatin in A549 cells cultured for 4 days in HS (n = 15 biologically independent samples per HS donor group, two-sided ANOVA). d, e, Metastatic properties of MDA-MB-231-luciferase cells cultured for 5 days in HS evaluated by immunoblots (d; n = 6 biologically independent samples per HS donor group) and lung colonization assay (e; n = 11 biologically independent samples, each the average of three mice used as technical replicates, per HS donor group, two-sided t-test); examples shown to the right. c, e, Data presented as mean ± s.e.m. For gel source data, see Supplementary

     確定不同血清產(chǎn)生的效果過后,，需要分析兩種血清的不同之處才能確定具體是那種因素導(dǎo)致的結(jié)果,。作者檢測了兩種血清的代謝物組成，發(fā)現(xiàn)只有三種代謝物——磷酸烯醇丙酮酸,、喹啉酸和甲基丙二酸(MMA)——在老年血清中持續(xù)增加,，這說明很可能是三種代謝物的增加促進的癌細胞的發(fā)展。然而,，用這三種代謝物處理癌細胞后只有MMA（主要是丙酸代謝的副產(chǎn)物）會引起完全的促進侵襲的EMT表型和促進侵襲蛋白的表達,。這樣的話研究對象就更加具體了。

MMA induces aggressive traits of cancer cells

甲基丙二酸誘導(dǎo)腫瘤細胞具有侵襲性

a, Concentrations of MMA in all HS samples (n = 30 biologically independent samples per HS donor group). b, Immunoblots of A549 cells treated with MMA for 10 days; representative images (n = 4 independent experiments). c, Transwell migration and invasion assays of MCF-10A cells treated with MMA for 10 days (n = 4 independent experiments). d, Lung colonization assay of MDA-MB-231-luciferase cells treated with MMA for 5 days (n = 10 mice per group; example mice shown to right). e–g, End-point serum MMA concentrations (e; n = 8 mice per group), bioluminescence intensity of the primary tumours (f, n = 9 mice per group), and metastases (g; n = 9 mice per group) in mice that were xenografted with MDA-MB-231-luciferase cells and subcutaneously injected with MMA daily. h, Kaplan–Meier curve of mice xenografted with MDA-MB-231-luciferase cells and treated with MMA either subcutaneously or through drinking water (n = 19 mice per experimental group). a, c–g, Mean ± s.e.m., two-sided t-test; h, Mantel–Cox test. For gel source data, see Supplementary Fig. 2.

      為了進一步研究MMA是怎樣誘發(fā)癌細胞的這種表型,，作者利用Gene set enrichment analysis (GSEA)實驗發(fā)現(xiàn)MMA可以誘導(dǎo)SOX4（一種不良預(yù)后標(biāo)志物,，有助于腫瘤增值和轉(zhuǎn)移形成，在多種侵襲性腫瘤中異常高表達,，并被認(rèn)為是EMT的主要調(diào)控因子）的表達,，通過驗證發(fā)現(xiàn)是MMA激活TGFβ信號從而誘導(dǎo)SOX4表達，進而引發(fā)侵襲性相關(guān)的轉(zhuǎn)錄重編程,，賦予癌細胞侵襲性,。 

MMA triggers pro-aggressive transcriptional reprogramming by activation of TGFβ signalling and consequent induction of SOX4

MMA 通過激活TGFβ信號產(chǎn)生SOX4誘導(dǎo)促進侵襲性轉(zhuǎn)錄重編程

a, b, Immunoblots of A549 cells treated with MMA for 10 days (a; n = 4 independent experiments) or HS for 4 days (b; n = 6 biologically independent samples, each the average of three mice used as technical replicates, per HS donor group). c, d, Lung colonization assay of MDA-MB-231-luciferase cells with SOX4 knockdown (shSOX4 no. 1 or no. 2) and treated with 5 mM MMA (c; n = 8 mice per group) or HS from old donors (d; n = 6 mice per group) for 5 days. shNT, non-specific shRNA. e, Levels of TGFβ-2 ligand in conditioned medium from A549 cells treated with 5 mM MMA (n = 4 independent experiments). f, g, TGFB2mRNA levels determined by qPCR (f; vehicle n = 5, MMA n = 8 mice) and immunoblots (g; representative images, n = 8 mice per group) in tumour samples from mice subcutaneously injected with the lower dose of MMA daily. h, Immunoblots of A549 cells treated with 5 mM MMA in the presence of TGFβ-neutralizing antibody; representative images (n = 4 independent experiments). c–f, Mean ± s.e.m., two-sided t-test. For gel source data, see Supplementary Fig. 2. ppSMAD3 S423/S425: SMAD3 phosphorylated on serine 423 and serine 425.

總之，MMA代謝物的積累架起了衰老和癌癥增殖之間的橋梁,，提示MMA是晚期癌的一個有前途的治療靶點,。

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嫌太長不愛看的看這：

甲基丙二酸(MMA)

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