Department of Oral and Maxillofacial Surgery, Kochi Medical School, Kochi University, Nankoku, Japan.
Department of Clinical Immunology, Kochi Medical School, Kochi University, Nankoku, Japan.
J Oral Pathol Med. 2022 Feb;51(2):126-133. doi: 10.1111/jop.13268. Epub 2021 Dec 19.
Constitutive activation of STAT3 promotes oncogenesis and growth of oral squamous cell carcinoma (OSCC). We investigated the mechanism of action of suppressor of cytokine signaling 1 (SOCS1), an endogenous inhibitor of JAK, as gene therapy for OSCC.
Antitumor effect of SOCS1 was compared to JAK inhibitor I by cell proliferation assay, cell cycle analysis, and apoptosis analysis in vitro. In addition, antitumor effect was evaluated using xenograft mouse models in vivo.
JAK inhibitor I inhibited the proliferation of KOSC2 cl3-43 or T3M-1 clone2 OSCC cell lines in vitro. While JAK inhibitor I arrested both cell lines at the G2/M phase, induction of apoptosis was observed in T3M-1 clone2 cells, but not KOSC2-cl3-43 cells. An adenoviral vector expressing SOCS1 (AdSOCS1) significantly decreased the proliferation of both OSCC cell lines and induced G2/M phase cell cycle arrest and apoptosis, suggesting that induction of apoptosis of KOSC2 cl3-43 cells by AdSOCS1 is regulated by the JAK/STAT independent pathway. Overexpression of SOCS1 inhibited activation of the JAK/STAT and p44/42 MAPK pathways, while JAK inhibitor I inhibited activation of the JAK/STAT pathway only. Consistently, expression of Mcl-1 was decreased by overexpression of SOCS1, but not JAK inhibitor I. Additionally, KOSC2 cl3-43 or T3M-1 clone2 OSCC cells were subcutaneously implanted in the flanks of two xenograft mouse models. As compared to a control adenovirus vector (AdLacZ), intratumor injection of AdSOCS1 significantly decreased the tumor volume and induced apoptosis in vivo.
SOCS1 gene therapy may be a beneficial approach for the treatment of OSCC.
STAT3 的组成性激活促进口腔鳞状细胞癌（OSCC）的发生和生长。我们研究了细胞因子信号转导抑制因子 1（SOCS1）作为 OSCC 基因治疗的作用机制，SOCS1 是 JAK 的内源性抑制剂。
通过细胞增殖测定、细胞周期分析和体外凋亡分析比较 SOCS1 与 JAK 抑制剂 I 的抗肿瘤作用。此外，还通过体内异种移植小鼠模型评估了抗肿瘤作用。
JAK 抑制剂 I 抑制 KOSC2 cl3-43 或 T3M-1 clone2 OSCC 细胞系的体外增殖。虽然 JAK 抑制剂 I 将这两个细胞系都阻滞在 G2/M 期，但 T3M-1 clone2 细胞中观察到细胞凋亡诱导，而 KOSC2-cl3-43 细胞中则没有。表达 SOCS1 的腺病毒载体（AdSOCS1）显著降低了两种 OSCC 细胞系的增殖，并诱导 G2/M 期细胞周期阻滞和凋亡，表明 AdSOCS1 诱导 KOSC2 cl3-43 细胞凋亡是通过 JAK/STAT 非依赖性途径调节的。SOCS1 的过表达抑制了 JAK/STAT 和 p44/42 MAPK 通路的激活，而 JAK 抑制剂 I 仅抑制了 JAK/STAT 通路的激活。同样，SOCS1 的过表达降低了 Mcl-1 的表达，但 JAK 抑制剂 I 没有。此外，将 KOSC2 cl3-43 或 T3M-1 clone2 OSCC 细胞皮下植入两个异种移植小鼠模型的侧翼。与对照腺病毒载体（AdLacZ）相比，肿瘤内注射 AdSOCS1 显著降低了肿瘤体积并在体内诱导了凋亡。
SOCS1 基因治疗可能是治疗 OSCC 的一种有益方法。
