六君子汤通过抑制 miR-34a/STAT3/IL-6R 反馈回路发挥强大的抗肿瘤活性，并调节抗肿瘤免疫。

Liujunzi decoction exerts potent antitumor activity in oesophageal squamous cell carcinoma by inhibiting miR-34a/STAT3/IL-6R feedback loop, and modifies antitumor immunity.

机构信息

Henan International Joint Laboratory of TCM Syndrome and Prescription in Signaling, Henan University of Chinese Medicine, Zhengzhou, Henan Province 450046, China; Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, Henan Province 450046, China; The Tumor Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan Province 450008, China.

出版信息

Phytomedicine. 2023 Mar;111:154672. doi: 10.1016/j.phymed.2023.154672. Epub 2023 Jan 13.

DOI:10.1016/j.phymed.2023.154672

PMID:36701994

Abstract

BACKGROUND

Liujunzi decoction (LJZD), a traditional herbal formula and one of the most commonly used adjuvant medications for the treatment of oesophageal squamous cell carcinoma (ESCC), exerts good antitumor and immunomodulatory activity. However, its specific mechanism of action remains largely unclear.

PURPOSE

In order to examine the potential primary and adjuvant antitumor mechanisms of LJZD, both in vitro and in vivo.

METHODS

IL-6 and miR-34a inhibitors were used to activate the miR-34a/STAT3/IL-6R feedback loop to observe the effects of LJZD. A humanised mouse model with a functional human immune system was constructed to evaluate the antitumor efficacy of LJZD in vivo on xenograft tumours, which was compared to that of the positive control drug anti-PD-1 monoclonal antibodies (mAb). Finally, a co-culture system of peripheral blood mononuclear and tumour cells in vitro was used to analyse the cytotoxic activity of LJZD on T cells.

RESULTS

LJZD significantly interfered with IL-6-induced activation of the miR-34a/STAT3/IL-6R feedback loop in ESCC by restoring the expression of the tumour suppressor miR-34a, and inhibited the proliferation of EC109 oesophageal cancer cells in a dose-dependant manner. Furthermore, LJZD effectively suppressed oesophageal tumour growth in vivo and alleviated organ injury and visceral index. Furthermore, LJZD boosted antitumor immunity by increasing IFN-γ expression and CD8tumour-infiltrating lymphocytes (TILs) infiltration in the peripheral blood and tumour tissues, respectively, which may be related to a decrease in PD-1, but not PD-L1 expression. Finally, we confirmed that LJZD strengthens the killing ability of T cells by suppressing PD-1 expression in a co-culture system in vitro.

CONCLUSION

LJZD exerts excellent antitumor effect by interfering with the miR-34a/STAT3/IL-6R feedback loop and augmenting antitumor immune responses. Which provides new insights into mechanisms for LJZD and sheds light on the multifaceted role of phytomedicine in cancer.

摘要

背景

六君子汤（LJZD）是一种传统的中草药配方，也是治疗食管鳞状细胞癌（ESCC）最常用的辅助药物之一，具有良好的抗肿瘤和免疫调节活性。然而，其具体的作用机制在很大程度上仍不清楚。

目的

为了研究 LJZD 的潜在的主要和辅助抗肿瘤机制，在体外和体内进行了研究。

方法

使用 IL-6 和 miR-34a 抑制剂激活 miR-34a/STAT3/IL-6R 反馈回路，观察 LJZD 的作用。构建了具有功能性人免疫系统的人源化小鼠模型，以评估 LJZD 在体内对异种移植肿瘤的抗肿瘤疗效，并与阳性对照药物抗 PD-1 单克隆抗体（mAb）进行比较。最后，在体外使用外周血单个核细胞和肿瘤细胞的共培养系统分析 LJZD 对 T 细胞的细胞毒性作用。

结果

LJZD 通过恢复肿瘤抑制 miR-34a 的表达，显著干扰了 ESCC 中 IL-6 诱导的 miR-34a/STAT3/IL-6R 反馈回路的激活，并呈剂量依赖性抑制 EC109 食管癌细胞的增殖。此外，LJZD 有效地抑制了体内食管肿瘤的生长，并减轻了器官损伤和内脏指数。此外，LJZD 通过增加外周血和肿瘤组织中 IFN-γ的表达和 CD8 肿瘤浸润淋巴细胞（TILs）的浸润，增强了抗肿瘤免疫，这可能与 PD-1 的表达降低有关，但与 PD-L1 的表达无关。最后，我们在体外共培养系统中证实，LJZD 通过抑制 PD-1 的表达增强了 T 细胞的杀伤能力。