Nrf2 expression in pancreatic stellate cells promotes progression of cancer.
Nrf2 expression in pancreatic stellate cells promotes progression of cancer.
复制标题
胰腺星状细胞中 Nrf2 的表达促进癌症的进展。
DOI：
10.1152/ajpgi.00120.2021
复制
发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Masamune A.
中科院分区：
文献类型：
--
作者：
Tanaka Y;Hamada S;Matsumoto R;Taguchi K;Yamamoto M;Masamune A.
先前在表达mukaryoK-ras/p53的小鼠模型（KPC小鼠）中发现，系统性Nrf 2缺失可减弱胰腺癌进展。在这项研究中，阐明了导致癌症进展迟缓的细胞类型。首先检查了人类胰腺癌，发现α-平滑肌肌动蛋白阳性细胞中NRF 2靶基因产物的表达升高，表明胰腺星状细胞（PSC）参与了这一过程。对来自Nrf 2缺失小鼠的原代培养的PSC进行更仔细的检查，发现细胞增殖性较低，并且保留了较低的迁移能力。Nrf 2缺失的PSC的条件培养基在胰腺癌细胞中表现出降低的生长刺激作用。KPC小鼠来源的胰腺癌细胞与野生型PSC共注射在免疫缺陷小鼠中比与Nrf 2缺失的PSC共注射的皮下肿瘤明显更大。这些结果表明，Nrf 2积极地促进PSC的功能，以维持KPC癌症进展，因此，表明PSC中的Nrf 2抑制可能在胰腺癌中具有治疗重要性。PSC中的Nrf 2缺失导致癌症促进作用减弱。PSC中的Nrf 2可能是胰腺癌的一个有吸引力的治疗靶点。
It was previously identified that systemicNrf2deletion attenuates pancreatic cancer progression in a mutantK-ras/p53-expressing mouse model (KPC mouse). In this study, the type of cell that is responsible for the retarded cancer progression was elucidated. Human pancreatic cancers were first examined, and elevated expression of NRF2-target gene products in α-smooth muscle actin-positive cells was found, suggesting that pancreatic stellate cells (PSCs) are involved in this process. Closer examination of primary cultured PSCs fromNrf2-deleted mice revealed that the cells were less proliferative and retained a lower migration capacity. The conditioned medium ofNrf2-deleted PSCs exhibited reduced growth-stimulating effects in pancreatic cancer cells. KPC mouse-derived pancreatic cancer cells coinjected with wild-type PSCs developed significantly larger subcutaneous tumors in immunodeficient mice than those coinjected withNrf2-deleted PSCs. These results demonstrate that Nrf2 actively contributes to the function of PSCs to sustain KPC cancer progression, thus, suggesting that Nrf2 inhibition in PSCs may be therapeutically important in pancreatic cancer.NEW & NOTEWORTHYThis study identified that Nrf2 contributes to PSC activation. Nrf2 deletion in PSCs resulted in attenuation of cancer-promoting role. Nrf2 in PSCs could be an attractive therapeutic target in pancreatic cancer.