Lim Whasun, Bae Hyocheol, Bazer Fuller W, Song Gwonhwa
Department of Biotechnology, Institute of Animal Molecular Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Republic of Korea.
Department of Animal Science, Center for Animal Biotechnology and Genomics, Texas A&M University, Texas, USA.
Biol Reprod. 2017 Jan 1;96(1):185-198. doi: 10.1095/biolreprod.116.142331.
Fibroblast growth factor 2 (FGF2) is a mitogen that induces proliferation, differentiation, and migration of cells, as well as angiogenesis and carcinogenesis via autocrine or paracrine actions. Fibroblast growth factor 2 expression is abundant in porcine conceptuses and endometrium during the estrous cycle and peri-implantation period of pregnancy. However, its intracellular actions in uterine epithelial cells have not been reported. The results of this study indicated abundant expression of FGFR1 and FGFR2 predominantly in uterine luminal and glandular epithelia during early pregnancy and that their expression decreased with increasing parity of the sows. Treatment of porcine uterine luminal epithelial (pLE) cells with FGF2 increased proliferation and DNA replication based on increases in proliferating cell nuclear antigen (PCNA) and initiation of G1/S phase progression. In addition, FGF2 increases phosphorylation of AKT, P70S6K, S6, ERK1/2, JNK, P38, and P90RSK in a time-dependent manner, and increases in their expression was suppressed by Wortmannin (a phosphatidylinositol 3-kinase [PI3K] inhibitor), U0126 (an ERK1/2 inhibitor), SP600125 (a JNK inhibitor), and SB203580 (a P38 inhibitor) based on western blot analyses. Also, the abundance of cytoplasmic p-AKT protein was decreased by Wortmannin and U0126, and p-ERK1/2 protein was reduced only by U0126. Furthermore, inhibition of each signal transduction protein reduced the ability of FGF2 to stimulate proliferation and migration of pLE cells. Collectively, these results indicate that activation of FGFR1 and FGFR2 by uterine- and endometrial-derived FGF2 stimulates PI3K/AKT and mitogen-activated protein kinase pathways for development of the porcine uterus and improvement of litter size.
成纤维细胞生长因子2（FGF2）是一种有丝分裂原，可通过自分泌或旁分泌作用诱导细胞增殖、分化和迁移，以及血管生成和癌变。在发情周期和妊娠植入前期，成纤维细胞生长因子2在猪的胚胎和子宫内膜中大量表达。然而，其在子宫上皮细胞中的细胞内作用尚未见报道。本研究结果表明，FGFR1和FGFR2在妊娠早期主要在子宫腔上皮和腺上皮中大量表达，且其表达随着母猪胎次的增加而降低。用FGF2处理猪子宫腔上皮（pLE）细胞，基于增殖细胞核抗原（PCNA）的增加和G1/S期进程的启动，增加了细胞增殖和DNA复制。此外，FGF2以时间依赖性方式增加AKT、P70S6K、S6、ERK1/2、JNK、P38和P90RSK的磷酸化，根据蛋白质印迹分析，渥曼青霉素（一种磷脂酰肌醇3激酶[PI3K]抑制剂）、U0126（一种ERK1/2抑制剂）、SP600125（一种JNK抑制剂）和SB203580（一种P38抑制剂）抑制了它们的表达增加。而且，渥曼青霉素和U0126降低了细胞质p-AKT蛋白的丰度，只有U0126降低了p-ERK1/2蛋白。此外，抑制每种信号转导蛋白降低了FGF2刺激pLE细胞增殖和迁移的能力。总的来说，这些结果表明，子宫和子宫内膜来源的FGF2激活FGFR1和FGFR2可刺激PI3K/AKT和丝裂原活化蛋白激酶途径，促进猪子宫发育并提高产仔数。
