Hubei University of Chinese Medicine, Wuhan, 430065, China.
Department of Nephrology, ChongQing JiangJin District Hospital of Chinese Medicine, Chongqing, 402260, China.
Clin Transl Oncol. 2023 Jul;25(7):2138-2152. doi: 10.1007/s12094-023-03093-w. Epub 2023 Feb 9.
The hypoxic tumor microenvironment and the maintenance of stem cells are relevant to the malignancy of prostate cancer (PCa). However, whether HIF-1α in the hypoxic microenvironment mediates the transformation of prostate cancer to a stem cell phenotype and the mechanism have not been elucidated.
Prostate cancer stem cells (PCSCs) from PC-3 cell lines were examined for the expression of CD44, CD133, ALDH1, HIF-1α, Notch1, and HES1. We observed the effect of knockdown HIF-1α in vitro and mice models and evaluated the impact of HIF-1α on the Notch1 pathway as well as stem cell dedifferentiation. The effects on sphere formation, cell proliferation, apoptosis, cell cycle, and invasive metastasis were evaluated.
In our study, hypoxia upregulated HIF-1α expression and induced a stem cell phenotype through activation of the Notch1 pathway, leading to enhanced proliferation, invasion, and migration of PCa PC-3 cells. The knockdown of HIF-1α significantly inhibited cell dedifferentiation and the ability to proliferate, invade and metastasize. However, the inhibitory effect of knocking down HIF-1α was reversed by Jagged1, an activator of the Notch1 pathway. These findings were further confirmed in vivo, where hypoxia could enhance the tumorigenicity of xenograft tumors by upregulating the expression of HIF-1α to activate the Notch1 pathway. In addition, the expression of HIF-1α and Notch1 was significantly increased in human PCa tissues, and high expression of HIF-1α correlated with the malignancy of PCa.
In a hypoxic environment, HIF-1α promotes PCa cell dedifferentiation to stem-like cell phenotypes by activating the Notch1 pathway and enhancing the proliferation and invasive capacity of PC-3 cells.
缺氧肿瘤微环境和干细胞的维持与前列腺癌（PCa）的恶性程度相关。然而，缺氧微环境中的 HIF-1α 是否介导前列腺癌向干细胞表型的转化及其机制尚不清楚。
从 PC-3 细胞系中检测前列腺癌干细胞（PCSCs）中 CD44、CD133、ALDH1、HIF-1α、Notch1 和 HES1 的表达。我们观察了体外和小鼠模型中敲低 HIF-1α 的效果，并评估了 HIF-1α 对 Notch1 通路以及干细胞去分化的影响。评估了对球体形成、细胞增殖、凋亡、细胞周期和侵袭转移的影响。
在我们的研究中，缺氧通过激活 Notch1 通路上调 HIF-1α 的表达并诱导干细胞表型，导致 PCa PC-3 细胞增殖、侵袭和迁移增强。敲低 HIF-1α 可显著抑制细胞去分化和增殖、侵袭和转移的能力。然而，Notch1 通路的激活剂 Jagged1 逆转了 HIF-1α 敲低的抑制作用。这些发现进一步在体内得到证实，其中缺氧通过上调 HIF-1α 的表达激活 Notch1 通路来增强异种移植肿瘤的致瘤性。此外，HIF-1α 和 Notch1 在人前列腺癌组织中的表达明显增加，HIF-1α 的高表达与前列腺癌的恶性程度相关。
在缺氧环境中，HIF-1α 通过激活 Notch1 通路促进 PCa 细胞去分化为干细胞样表型，并增强 PC-3 细胞的增殖和侵袭能力。
