P63 缺失和 CDX2 过表达导致小鼠食管上皮出现类似 Barrett 的化生。
P63 Deficiency and CDX2 Overexpression Lead to Barrett's-Like Metaplasia in Mouse Esophageal Epithelium.
机构信息
Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400045, China.
Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, 700 George St, Durham, NC, 27707, USA.
出版信息
Dig Dis Sci. 2021 Dec;66(12):4263-4273. doi: 10.1007/s10620-020-06756-8. Epub 2021 Jan 19.
BACKGROUND
The cellular origin and molecular mechanisms of Barrett's esophagus (BE) are still controversial. Trans-differentiation is a mechanism characterized by activation of the intestinal differentiation program and inactivation of the squamous differentiation program.
AIMS
Renal capsule grafting (RCG) was used to elucidate whether CDX2 overexpression on the basis of P63 deficiency in the esophageal epithelium may generate intestinal metaplasia.
METHODS
P63;Villin-Cdx2 embryos were generated by crossing P63 mice with Villin-Cdx2 mice. E18.5 esophagus was xenografted in a renal capsule grafting (RCG) model. At 1, 2, or 4 weeks after RCG, the mouse esophagus was immunostained for a proliferation marker (BrdU), squamous transcription factors (SOX2, PAX9), squamous differentiation markers (CK5, CK4, and CK1), intestinal transcription factors (CDX1, HNF1α, HNF4α, GATA4, and GATA6), intestinal columnar epithelial cell markers (A33, CK8), goblet cell marker (MUC2, TFF3), Paneth cell markers (LYZ and SOX9), enteroendocrine cell marker (CHA), and Tuft cell marker (DCAMKL1).
RESULTS
The P63;Villin-Cdx2 RCG esophagus was lined with proliferating PAS/AB+ cuboidal cells and formed an intestinal crypt-like structure. The goblet cell markers (TFF3 and MUC2) and intestinal transcription factors (CDX1, HNF1α, HNF4α, GATA4, and GATA6) were expressed although no typical morphology of goblet cells was observed. Other intestinal cell markers including enteroendocrine cell marker (CHA), Paneth cell markers (LYZ and Sox9), and intestinal secretory cell marker (UEA/WGA) were also expressed in the P63;Villin-Cdx2 RCG esophagus. Squamous cell markers (PAX9 and SOX2) were also expressed, suggesting a transitional phenotype.
CONCLUSION
CDX2 overexpression on the basis of P63 deficiency in esophageal epithelial cells induces Barrett's-like metaplasia in vivo. Additional factors may be needed to drive this transitional phenotype into full-blown BE.
背景
巴雷特食管（BE）的细胞起源和分子机制仍存在争议。转分化是一种特征为肠分化程序激活和鳞状分化程序失活的机制。
目的
本研究通过肾包膜移植（RCG），探讨食管上皮中 P63 缺乏基础上 CDX2 的过表达是否可能产生肠化生。
方法
通过将 P63 小鼠与 Villin-Cdx2 小鼠杂交，生成 P63;Villin-Cdx2 胚胎。E18.5 食管进行肾包膜移植（RCG）模型异种移植。RCG 后 1、2 或 4 周，对小鼠食管进行增殖标志物（BrdU）、鳞状转录因子（SOX2、PAX9）、鳞状分化标志物（CK5、CK4、CK1）、肠转录因子（CDX1、HNF1α、HNF4α、GATA4、GATA6）、肠柱状上皮细胞标志物（A33、CK8）、杯状细胞标志物（MUC2、TFF3）、潘氏细胞标志物（LYZ 和 SOX9）、肠内分泌细胞标志物（CHA）和微绒毛细胞标志物（DCAMKL1）免疫染色。
结果
P63;Villin-Cdx2 RCG 食管被增殖的 PAS/AB+立方细胞覆盖，并形成肠隐窝样结构。虽然没有观察到典型的杯状细胞形态，但表达了杯状细胞标志物（TFF3 和 MUC2）和肠转录因子（CDX1、HNF1α、HNF4α、GATA4、GATA6）。在 P63;Villin-Cdx2 RCG 食管中还表达了其他肠细胞标志物，包括肠内分泌细胞标志物（CHA）、潘氏细胞标志物（LYZ 和 Sox9）和肠分泌细胞标志物（UEA/WGA）。鳞状细胞标志物（PAX9 和 SOX2）也有表达，提示存在过渡表型。
结论
食管上皮细胞中 P63 缺乏基础上 CDX2 的过表达可在体内诱导类似巴雷特的化生。可能需要其他因素将这种过渡表型转变为完全的 BE。
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