Division of Vascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.
Int J Mol Sci. 2022 May 4;23(9):5134. doi: 10.3390/ijms23095134.
Hypoxia regulates fibroblast function by changing intracellular signaling and secretion factors, that influence the states of nearby cells. In this work, we investigated how medium (CM) from human adult dermal fibroblasts (HDFs) cultured in normoxic and hypoxic conditions affected cervical cancer (HeLa) cells. The HeLa cells showed decreased cell viability, increased apoptosis, and cell cycle arrest in response to CM from hypoxic-cultured HDFs (H-CM) compared with CM from normoxic-cultured HDFs (N-CM). Among the proteins up-regulated (>2-fold) in H-CM compared with N-CM, lymphotoxin-beta receptor (LTBR) decreased the viability of HeLa cells. Among the intracellular proteins down-regulated (>2-fold) in HeLa cells treated with H-CM compared with N-CM, the most enriched biological process GO term and KEGG pathway were protein deubiquitination and hsa05166:HTLV-I infection, respectively. In the protein−protein interaction network of intracellular proteins with altered expression (>2-fold), 1 up-regulated (TNF) and 8 down-regulated (ESR1, MCL1, TBP, CD19, LCK, PCNA, CHEK1, and POLA1) hub proteins were defined. Among the down-regulated hub proteins, the most enriched biological process GO term and KEGG pathway were leading strand elongation and hsa05166:HTLV-I infection, respectively. This study reveals that H-CM had stronger anti-cancer effects on cervical cancer cells than N-CM and induced intracellular signaling patterns related to those enhanced anti-cancer effects.
缺氧通过改变细胞内信号和分泌因子来调节成纤维细胞的功能，这些因子会影响附近细胞的状态。在这项工作中，我们研究了在常氧和低氧条件下培养的人成纤维细胞（HDF）的培养基（CM）如何影响宫颈癌（HeLa）细胞。与常氧培养的 HDF 的 CM（N-CM）相比，低氧培养的 HDF 的 CM（H-CM）使 HeLa 细胞的活力降低、凋亡增加和细胞周期停滞。与 N-CM 相比，H-CM 中上调（>2 倍）的蛋白质中，淋巴毒素-β受体（LTBR）降低了 HeLa 细胞的活力。与 N-CM 相比，在用 H-CM 处理的 HeLa 细胞中下调（>2 倍）的细胞内蛋白质中，最丰富的生物学过程 GO 术语和 KEGG 途径分别是蛋白质去泛素化和 hsa05166：HTLV-I 感染。在表达发生改变（>2 倍）的细胞内蛋白质的蛋白质-蛋白质相互作用网络中，定义了 1 个上调（TNF）和 8 个下调（ESR1、MCL1、TBP、CD19、LCK、PCNA、CHEK1 和 POLA1）的枢纽蛋白。在下调的枢纽蛋白中，最丰富的生物学过程 GO 术语和 KEGG 途径分别是先导链延伸和 hsa05166：HTLV-I 感染。本研究揭示，H-CM 对宫颈癌细胞的抗癌作用强于 N-CM，并诱导与增强抗癌作用相关的细胞内信号模式。
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