Cummings School of Veterinary Medicine, Tufts University, North Grafton, Massachusetts, USA.
College of Veterinary Medicine, The Ohio State University, Columbus, Ohio, USA.
Vet Comp Oncol. 2022 Dec;20(4):817-824. doi: 10.1111/vco.12841. Epub 2022 Jul 11.
Signal transducer and activator of transcription 3 (STAT3) dysregulation has been characterized in canine OS, with previous data suggesting that constitutive STAT3 activation contributes to survival and proliferation in OS cell lines in vitro. Recently, the contribution of STAT3 to tumour metabolism has been described across several tumour histologies, and understanding the metabolic implications of STAT3 loss may elucidate novel therapeutic approaches with synergistic activity. The objective of this work was to characterize metabolic benchmarks associated with STAT3 loss in canine OS. STAT3 expression and activation was evaluated using western blotting in canine OS cell lines OSCA8 and Abrams. STAT3 was deleted from these OS cell lines using CRISPR-Cas9, and the effects on proliferation, invasion and metabolism (respirometry, intracellular lactate) were determined. Loss of STAT3 was associated with decreased basal and compensatory glycolysis in canine OS cell lines, without modulation of cellular proliferation. Loss of STAT3 also resulted in diminished invasive capacity in vitro. Interestingly, the absence of STAT3 did not impact sensitivity to doxorubicin in vitro. Our data demonstrate that loss of STAT3 modulates features of aerobic glycolysis in canine OS impacting capacities for cellular invasions, suggesting a role for this transcription factor in metastasis.
信号转导子和转录激活子 3（STAT3）失调已在犬骨肉瘤（OS）中得到表征，先前的数据表明，组成性 STAT3 激活有助于 OS 细胞系在体外的存活和增殖。最近，STAT3 对几种肿瘤组织学的肿瘤代谢的贡献已经被描述，了解 STAT3 缺失对代谢的影响可能阐明具有协同作用的新的治疗方法。这项工作的目的是表征与犬骨肉瘤中 STAT3 缺失相关的代谢基准。使用蛋白质印迹法在犬骨肉瘤细胞系 OSCA8 和 Abrams 中评估 STAT3 的表达和激活。使用 CRISPR-Cas9 从这些骨肉瘤细胞系中删除 STAT3，并确定其对增殖、侵袭和代谢（呼吸测定法、细胞内乳酸）的影响。STAT3 的缺失与犬骨肉瘤细胞系中基础和代偿性糖酵解的降低有关，而不会影响细胞增殖。STAT3 的缺失也导致体外侵袭能力的降低。有趣的是，STAT3 的缺失并不影响体外阿霉素的敏感性。我们的数据表明，STAT3 的缺失调节了犬骨肉瘤中有氧糖酵解的特征，影响了细胞侵袭的能力，提示该转录因子在转移中发挥作用。
