高脂飲食促進肺腺癌腫瘤生長機制探討

Abstract

飲食習慣與癌症的發生明顯相關，據估計約30%的癌症病例與飲食有關。某些具抗癌效果的營養素被發現可抑制癌細胞生長的路徑，相反的部分脂質、低密度膽固醇及脂肪分泌的激素會促進癌細胞生長，於大腸癌、乳癌、前列腺癌等曾被報導，但在肺癌的探討相當有限且機制尚不明瞭。我們利用基因轉殖小鼠以藥物促使突變型表皮生長因子受體L858R表現作為肺腺癌動物模式，小鼠另外餵食高脂飲食及正常飲食以比較肺部腫瘤的生長情形，以及後續蛋白及基因的表現分析。結果顯示餵食高脂飲食的肺癌小鼠其腫瘤體積較大，Ki67的基因表現也顯著上升。利用RNA定序分析全基因表現發現高脂及正常飲食的肺腫瘤小鼠之基因表現主要差異在細胞分裂的功能，經qPCR確認ROS1基因表現在高脂飲食的肺腫瘤小鼠中顯著上升，且與腫瘤大小有高度正相關 (R=0.7058, p=0.0033)，然而ROS1蛋白磷酸化及其下游訊號無明顯差異。此外，FOXM1基因表現量亦在高脂飲食的肺腫瘤顯著上升，其功能已有促進腫瘤生長的報導。另一方面，在餵食野生種小鼠高脂飲食可使鼠蹊部白脂肪的TIMP1、pentraxin3和IL-6分泌量顯著上升，亦與RNA定序結果不謀而合。Kaplan-Meier 生存分析顯示高表現TIMP1或IL-6的肺腺癌患者其總存活期顯著下降。未來可用重組蛋白或抑制劑測試癌細胞的生長變化，以期能找出高脂飲食促使肺腫瘤生長的關鍵並進而應用於臨床。

Diet is attributed to about 30% of risk factors of cancers. Some nutrients with anti-tumor effect is also known for inhibition of signaling pathway related to tumor formation. In contrast, specific lipid uptake, low-density lipoprotein cholesterol and cytokine produced by adipose tissue can induce cancer cells proliferation and reported to correlate with several cancers. However, investigation of lung cancer and diet are limited and the mechanism is not clarified yet. We have bred inducible transgenic mice with spontaneous lung cancer formation driven by mutant EGFRL858R for animal model of lung adenocarcinoma. Lung tissues were harvested for hematoxylin and eosin (HE) stain, immunohistochemical (IHC) stain, western blotting and RNA for whole-genome transcriptomic analysis. Mice fed with high-fat diet and tumor induction (LC-HFD group) had larger tumor burden than regular-diet group (LC-RD) in observation of HE, IHC staining for Ki67 and lung weight. Gene set enrichment analysis of RNA sequencing revealed that the gene expression related to the function of cell division was more enhanced in LC-HFD than LC-RD. In addition, expression of ROS1 gene in LC-HFD was also increased significantly and highly correlated to tumor burden. However, there was no obvious phosphorylated ROS1 protein in western blotting and activation of downstream signals. The sequencing result also indicated that FOXM1 expression increased in LC-HFD, a transcription factor that has been known for promoting tumor growth. Tumor progression induced by high-fat diet may be triggered by FOXM1 rather than ROS1. On the other hand, TIMP1, pentraxin3, and IL-6 expression from inguinal white adipose tissue (iWAT) of high-fat diet treated wild-type mice were significantly upregulated, complying with the result of iWAT RNA sequencing. Kaplan-Meier plot showed high expression of TIMP1 or IL-6 was associated with lower overall survival in patients with lung adenocarcinoma. In order to find out the key leads high-fat diet promoting tumor progression, it is suggested to utilize recombinant protein or inhibitor for in vitro and in vivo assay to clarify the underlying mechanism in future.