Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, 710032, China.
State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, 710032, China.
Sci Rep. 2017 Mar 31;7:45648. doi: 10.1038/srep45648.
Pioneering epidemiological work has established strong association of sedentary lifestyle and obesity with the risk of colorectal cancer, while the detailed underlying mechanism remains unknown. Here we show that Hotair (HOX transcript antisense RNA) is a pro-adipogenic long non-coding RNA highly expressed in gluteal-femoral fat over other fat depots. Hotair knockout in adipose tissue results in gluteal-femoral fat defect. Squeeze of the gluteal-femoral fat induces intestinal proliferation in wildtype mice, while not in Hotair knockout mice. Mechanistically, squeeze of the gluteal-femoral fat induces exosomal Hotair secretion mainly by transcriptional upregulation of Hotair via NFκB. And increased exosomal Hotair in turn circulates in the blood and is partially endocytosed by the intestine, finally promoting the stemness and proliferation of intestinal stem/progenitor cells via Wnt activation. Clinically, obese subjects with sedentary lifestyle have much higher exosomal HOTAIR expression in the serum. These findings establish that sedentary lifestyle promotes exosomal Hotair release from the gluteal-femoral fat, which in turn facilitates intestinal stem and/or progenitor proliferation, raising a possible link between sedentary lifestyle with colorectal tumorigenesis.
开创性的流行病学研究已经确立了久坐的生活方式和肥胖与结直肠癌风险之间的强烈关联，而其详细的潜在机制尚不清楚。在这里，我们表明 Hotair（HOX 转录反义 RNA）是一种促脂肪生成的长非编码 RNA，在臀股脂肪中高度表达，而在其他脂肪组织中表达较低。脂肪组织中的 Hotair 敲除会导致臀股脂肪缺陷。臀股脂肪的挤压会诱导野生型小鼠的肠道增殖，而不会诱导 Hotair 敲除小鼠的肠道增殖。在机制上，臀股脂肪的挤压通过 NFκB 主要通过转录上调 Hotair 诱导外泌体 Hotair 的分泌。并且增加的外泌体 Hotair 反过来在血液中循环，并被肠道部分内吞，最终通过 Wnt 激活促进肠道干细胞/祖细胞的干性和增殖。临床上，久坐生活方式的肥胖受试者血清中的外泌体 HOTAIR 表达水平更高。这些发现确立了久坐的生活方式促进了臀股脂肪中外泌体 Hotair 的释放，进而促进了肠道干细胞和/或祖细胞的增殖，这可能为久坐的生活方式与结直肠肿瘤发生之间建立了联系。
