Giampietri Claudia, Tomaipitinca Luana, Scatozza Francesca, Facchiano Antonio
Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Sapienza University of Rome, Rome, Italy.
Istituto Dermopatico dell'Immacolata - Istituto di Ricovero e Cura a Carattere Scientifico, IDI-IRCCS, Rome, Italy.
JMIR Cancer. 2020 May 19;6(1):e16974. doi: 10.2196/16974.
Publicly available genomic and transcriptomic data in searchable databases allow researchers to investigate specific medical issues in thousands of patients. Many studies have highlighted the role lipids play in cancer initiation and progression and reported nutritional interventions aimed at improving prognosis and survival. Therefore, there is an increasing interest in the role that fat intake may play in cancer. It is known that there is a relationship between BMI and survival in patients with cancer, and that there is an association between a high-fat diet and increased cancer risk. In some cancers, such as colorectal cancer, obesity and high fat intake are known to increase the risk of cancer initiation and progression. On the contrary, in patients undergoing treatment for melanoma, a higher BMI unexpectedly acts as a protective factor rather than a risk factor; this phenomenon is known as the obesity paradox.
We aimed to identify the molecular mechanism underlying the obesity paradox, with the expectation that this could indicate new effective strategies to reduce risk factors and improve protective approaches.
In order to determine the genes potentially involved in this process, we investigated the expression values of lipid-related genes in patients with melanoma or colorectal cancer. We used available data from 2990 patients from 3 public databases (IST [In Silico Transcriptomics] Online, GEO [Gene Expression Omnibus], and Oncomine) in an analysis that involved 3 consecutive validation steps. Of this group, data from 1410 individuals were analyzed in the IST Online database (208 patients with melanoma and 147 healthy controls, as well as 991 patients with colorectal cancer and 64 healthy controls). In addition, 45 melanoma, 18 nevi, and 7 healthy skin biopsies were analyzed in another database, GEO, to validate the IST Online data. Finally, using the Oncomine database, 318 patients with melanoma (312 controls) and 435 patients with colorectal cancer (445 controls) were analyzed.
In the first and second database investigated (IST Online and GEO, respectively), patients with melanoma consistently showed significantly (P<.001) lower expression levels of 4 genes compared to healthy controls: CD36, MARCO, FABP4, and FABP7. This strong reduction was not observed in patients with colorectal cancer. An additional analysis was carried out on a DNA-TCGA data set from the Oncomine database, further validating CD36 and FABP4.
The observed lower expression of genes such as CD36 and FABP4 in melanoma may reduce the cellular internalization of fat and therefore make patients with melanoma less sensitive to a high dietary fat intake, explaining in part the obesity paradox observed in patients with melanoma.
可搜索数据库中公开的基因组和转录组数据使研究人员能够在数千名患者中研究特定的医学问题。许多研究强调了脂质在癌症发生和发展中的作用，并报道了旨在改善预后和生存率的营养干预措施。因此，人们对脂肪摄入在癌症中可能发挥的作用越来越感兴趣。已知体重指数（BMI）与癌症患者的生存率之间存在关联，并且高脂饮食与癌症风险增加之间存在关联。在某些癌症中，如结直肠癌，肥胖和高脂肪摄入会增加癌症发生和发展的风险。相反，在接受黑色素瘤治疗的患者中，较高的BMI出人意料地起到保护因素而非风险因素的作用；这种现象被称为肥胖悖论。
我们旨在确定肥胖悖论背后的分子机制，期望这能指明降低风险因素和改进保护方法的新有效策略。
为了确定可能参与此过程的基因，我们研究了黑色素瘤或结直肠癌患者中脂质相关基因的表达值。我们使用了来自3个公共数据库（IST [在线计算机转录组学]、GEO [基因表达综合数据库]和Oncomine）的2990名患者的可用数据，该分析涉及3个连续的验证步骤。在这组数据中，对IST在线数据库中的1410名个体的数据进行了分析（208名黑色素瘤患者和147名健康对照，以及991名结直肠癌患者和64名健康对照）。此外，在另一个数据库GEO中分析了45份黑色素瘤、18份痣和7份健康皮肤活检样本，以验证IST在线数据库的数据。最后，使用Oncomine数据库，对318名黑色素瘤患者（312名对照）和435名结直肠癌患者（445名对照）进行了分析。
在最初研究的两个数据库（分别为IST在线数据库和GEO数据库）中，与健康对照相比，黑色素瘤患者始终显示出4个基因的表达水平显著降低（P<.001）：CD36、MARCO、FABP4和FABP7。结直肠癌患者未观察到这种明显的降低。对来自Oncomine数据库的DNA-TCGA数据集进行了额外分析，进一步验证了CD36和FABP4。
在黑色素瘤中观察到的CD36和FABP4等基因的较低表达可能会减少脂肪的细胞内吞作用，因此使黑色素瘤患者对高膳食脂肪摄入不太敏感，这部分解释了在黑色素瘤患者中观察到的肥胖悖论。
