Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.
Institute of Biotechnology, National Taiwan University, Taipei, Taiwan.
Clin Transl Med. 2022 Feb;12(2):e606. doi: 10.1002/ctm2.606.
Protein disulfide isomerases a4 (Pdia4) is known to be involved in cancer development. Our previous publication showed that Pdia4 positively promotes cancer development via its inhibition of procaspase-dependent apoptosis in cancer cells. However, nothing is known about its role in the cancer microenvironment.
Here, we first found that Pdia4 expression in lung cancer was negatively correlated with patient survival. Next, we investigated the impact of host Pdia4 in stromal cells during cancer development. We showed that Pdia4 was expressed at a low level in stromal cells, and this expression was up-regulated akin to its expression in cancer cells. This up-regulation was stimulated by tumour cell-derived stimuli. Genetics studies in tumour-bearing wild-type and Pdia4 mice showed that host Pdia4 promoted lung cancer development in the mice via cancer stroma. This promotion was abolished in Rag1 mice which lacked T and B cells. This promotion could be restored once T and B cells were added back to Rag1 mice. In addition, host Pdia4 positively regulated the number and immunosuppressive function of stromal cells. Mechanistic studies showed that host Pdia4 positively controlled the Stat3/Vegf pathway in T and B lymphocytes via its stabilization of activated Stat3 in a Thioredoxin-like domain (CGHC)-dependent manner.
These findings identify Pdia4 as a possible target for intervention in cancer stroma, suggesting that targeting Pdia4 in cancer stroma is a promising anti-cancer approach.
蛋白质二硫键异构酶 A4（Pdia4）已知参与癌症的发展。我们之前的研究表明，Pdia4 通过抑制癌细胞中依赖半胱天冬酶的凋亡来促进癌症的发展。然而，其在肿瘤微环境中的作用尚不清楚。
首先，我们发现肺癌中 Pdia4 的表达与患者的生存呈负相关。接下来，我们研究了宿主 Pdia4 在癌症发展过程中对基质细胞的影响。结果表明，基质细胞中 Pdia4 的表达水平较低，且其表达水平类似地在上皮细胞中上调。这种上调受到肿瘤细胞衍生刺激的刺激。在荷瘤野生型和 Pdia4 敲除小鼠的遗传研究中，宿主 Pdia4 通过肿瘤基质促进了小鼠的肺癌发展。在缺乏 T 和 B 细胞的 Rag1 小鼠中，这种促进作用被消除。一旦向 Rag1 小鼠中添加 T 和 B 细胞，这种促进作用就可以恢复。此外，宿主 Pdia4 还可积极调节基质细胞的数量和免疫抑制功能。机制研究表明，宿主 Pdia4 通过其在 Trx 样结构域（CGHC）依赖性方式稳定激活的 Stat3，积极调控 T 和 B 淋巴细胞中的 Stat3/VEGF 通路。
这些发现确定了 Pdia4 作为癌症基质干预的一个可能靶点，提示靶向癌症基质中的 Pdia4 是一种有前途的抗癌方法。
