Robinson Prema, Montoya Kelsey, Magness Emily, Rodriguez Emma, Villalobos Viviana, Engineer Nikita, Yang Peng, Bharadwaj Uddalak, Eckols Thomas Kris, Tweardy David John
Department of Infectious Diseases, Infection Control & Employee Health, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
Cancers (Basel). 2023 May 30;15(11):2977. doi: 10.3390/cancers15112977.
Inflammatory bowel disease (IBD) predisposes to colorectal cancer (CRC). In the current studies, we used the dextran sodium sulfate (DSS) murine model of colitis, which is widely used in preclinical studies, to determine the contribution of STAT3 to IBD. STAT3 has two isoforms: (STAT3 α; which has pro-inflammatory and anti-apoptotic functions, and STAT3β; which attenuates the effects of STAT3α). In the current study, we determined the contribution of STAT3 to IBD across all tissues by examining DSS-induced colitis in mice that express only STAT3α and in mice treated with TTI-101, a direct small-molecule inhibitor of both isoforms of STAT3.
We examined mortality, weight loss, rectal bleeding, diarrhea, colon shortening, apoptosis of colonic CD4+ T-cells, and colon infiltration with IL-17-producing cells following 7-day administration of DSS (5%) to transgenic STAT3α knock-in (STAT3β-deficient; ΔβΔβ) mice and wild-type (WT) littermate cage control mice. We also examined the effect of TTI-101 on these endpoints in DSS-induced colitis in WT mice.
Each of the clinical manifestations of DSS-induced colitis examined was exacerbated in ΔβΔβ transgenic versus cage-control WT mice. Importantly, TTI-101 treatment of DSS-administered WT mice led to complete attenuation of each of the clinical manifestations and also led to increased apoptosis of colonic CD4+ T cells, reduced colon infiltration with IL-17-producing cells, and down-modulation of colon mRNA levels of STAT3-upregulated genes involved in inflammation, apoptosis resistance, and colorectal cancer metastases.
Thus, small-molecule targeting of STAT3 may be of benefit in treating IBD and preventing IBD-associated colorectal cancer.
炎症性肠病（IBD）易患结直肠癌（CRC）。在当前研究中，我们使用葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎模型（该模型广泛应用于临床前研究）来确定信号转导和转录激活因子3（STAT3）在IBD中的作用。STAT3有两种异构体：（STAT3α，具有促炎和抗凋亡功能；以及STAT3β，可减弱STAT3α的作用）。在本研究中，我们通过检测仅表达STAT3α的小鼠以及用STAT3两种异构体的直接小分子抑制剂TTI-101处理的小鼠中DSS诱导的结肠炎，来确定STAT3在所有组织中对IBD的作用。
我们对转基因STAT3α敲入（STAT3β缺陷；ΔβΔβ）小鼠和野生型（WT）同窝对照小鼠给予5% DSS处理7天，之后检测死亡率、体重减轻、直肠出血、腹泻、结肠缩短、结肠CD4+ T细胞凋亡以及产生IL-17细胞在结肠的浸润情况。我们还检测了TTI-101对WT小鼠DSS诱导结肠炎这些终点指标的影响。
与同窝对照WT小鼠相比，ΔβΔβ转基因小鼠中检测的DSS诱导结肠炎的每种临床表现均加重。重要的是，对给予DSS的WT小鼠用TTI-101治疗导致每种临床表现完全减轻，还导致结肠CD4+ T细胞凋亡增加、产生IL-17细胞在结肠的浸润减少，以及与炎症、抗凋亡和结直肠癌转移相关的STAT3上调基因的结肠mRNA水平下调。
因此，对STAT3进行小分子靶向治疗可能有助于治疗IBD并预防IBD相关的结直肠癌。
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