Department of Human Anatomy, Basic College of Medical Sciences, Jilin University, Changchun, Jilin, P.R., China.
Eur Rev Med Pharmacol Sci. 2019 Nov;23(22):9965-9977. doi: 10.26355/eurrev_201911_19563.
Peroxisome proliferator-activated receptor γ (PPARγ) regulates fatty acid storage and glucose metabolism. Recently, PPARγ has been reported to be involved in cancer. The present study reported a PPARγ consensus binding site (AGGTCA) in the ptprf promoter and identified a strong association between PPARγ and PTPRF expression, as well as their tumor suppressor roles in a v-Ha-Ras-induced model of breast cancer.
The prognostic potential of PPARγ was assessed with a KM analysis of raw data from 3,951 breast cancer patients. The expression of PPARγ and PTPRF in the rat breast cancer cell lines was detected by Western blot and qPCR. The impact of PPARγ on cancer cell migration, invasion, and growth was confirmed using cell migration assay, transwell cell invasion assay, tri-dimensional soft agar culture, respectively. The binding of PPARγ with the ptprf promoter was then examined using electrophoretic mobility shift assay. The inhibitory effect of PPARγ on tumor growth was then examined in mouse tumor model in vivo.
It was identified that PPARγ expression is lost in the aggressive v-Ha-Ras-induced breast cancer cell line FE1.2 but highly expressed in less malignant FE1.3 cells. Exogenous expression of PPARγ in FE1.2 cells (FE1.2-PPARγhi) resulted in a marked inhibition of proliferation compared with that in FE1.2-Vector control group. FE1.2-PPARγhi cells also exhibited reduced migration, invasion, and colony formation abilities compared with those of the controls. The PPARγ agonist rosiglitazone also suppressed the malignant properties of FE1.2 cells. Protein tyrosine phosphatase receptor F (PTPRF), a downstream target of PPARγ, was markedly induced in FE1.2-PPARγhi cells. A PPARγ consensus binding site (AGGTCA) was identified in the ptprf promoter, and an electrophoretic mobility shift assay confirmed that PPARγ bind to this promoter. Similar to the effect of vector-mediated overexpression of PPARγ, ectopic overexpression of PTPRF in FE1.2 cells led to reduced proliferation. Furthermore, a PPARγ antagonist (GW9662) and PTP inhibitor (NSC87877) abrogated the suppressive function of PPARγ and PTPRF in FE1.2 cells, respectively. PPARγ overexpression or activation suppressed the progression and distant organ metastasis of breast cancer cells in a NOD/SCID mouse model.
These results suggest that PPARγ inhibits tumor cell proliferation, at least in part, through direct regulation of the ptprf gene and that PPARγ is a potential target for breast cancer treatment.
过氧化物酶体增殖物激活受体 γ（PPARγ）调节脂肪酸储存和葡萄糖代谢。最近，有报道称 PPARγ 参与了癌症。本研究在 ptprf 启动子中报告了一个 PPARγ 共识结合位点（AGGTCA），并鉴定了 PPARγ 与 PTPRF 表达之间的强相关性，以及它们在 v-Ha-Ras 诱导的乳腺癌模型中的肿瘤抑制作用。
使用来自 3951 名乳腺癌患者的原始数据的 KM 分析评估了 PPARγ 的预后潜力。通过 Western blot 和 qPCR 检测大鼠乳腺癌细胞系中 PPARγ 和 PTPRF 的表达。使用细胞迁移测定、Transwell 细胞侵袭测定和三维软琼脂培养分别证实了 PPARγ 对癌细胞迁移、侵袭和生长的影响。然后使用电泳迁移率变动测定法检查 PPARγ 与 ptprf 启动子的结合。然后在体内小鼠肿瘤模型中检查了 PPARγ 对肿瘤生长的抑制作用。
鉴定出 PPARγ 表达在侵袭性 v-Ha-Ras 诱导的乳腺癌细胞系 FE1.2 中丢失，但在恶性程度较低的 FE1.3 细胞中高度表达。FE1.2 细胞中 PPARγ 的外源性表达（FE1.2-PPARγhi）与 FE1.2-载体对照组相比，增殖明显受到抑制。FE1.2-PPARγhi 细胞的迁移、侵袭和集落形成能力也降低。PPARγ 激动剂罗格列酮也抑制了 FE1.2 细胞的恶性特性。PPARγ 的下游靶蛋白蛋白酪氨酸磷酸酶受体 F（PTPRF）在 FE1.2-PPARγhi 细胞中明显诱导。在 ptprf 启动子中鉴定出一个 PPARγ 共识结合位点（AGGTCA），电泳迁移率变动测定法证实 PPARγ 与该启动子结合。与载体介导的 PPARγ 过表达的作用相似，FE1.2 细胞中 PTPRF 的异位过表达导致增殖减少。此外，PPARγ 拮抗剂（GW9662）和 PTP 抑制剂（NSC87877）分别消除了 PPARγ 和 PTPRF 在 FE1.2 细胞中的抑制功能。PPARγ 过表达或激活抑制了 NOD/SCID 小鼠模型中乳腺癌细胞的进展和远处器官转移。
这些结果表明，PPARγ 通过直接调节 ptprf 基因抑制肿瘤细胞增殖，至少部分如此，并且 PPARγ 是乳腺癌治疗的潜在靶点。
