Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan.
Chinese Medicine Research Center, China Medical University, Taichung, Taiwan.
Oncogene. 2022 Feb;41(7):997-1010. doi: 10.1038/s41388-021-02136-2. Epub 2022 Jan 1.
Triple negative breast cancer (TNBC) possesses poor prognosis mainly due to lack of effective endocrine or targeted therapies, aggressive nature and high rate of chemoresistance. Cancer stem cells (CSCs) are considered to play critical roles in cancer recurrence and chemoresistance. THEMIS2 was identified as the sole common elevated gene in three triple negative breast cancer (TNBC) and two ovarian CSC lines. We discovered an intrinsic signaling scaffold function of THEMIS2, which acts as a novel regulator of cancer stemness in promoting multiple cancer stemness properties including sphere formation, stemness markers expression, chemoresistance and tumorigenicity with low numbers of cancer cells implantation. For the first time, we demonstrated that THEMIS2 specifically enhanced MET activating phosphorylation by suppressing the association of protein-tyrosine phosphatases 1B (PTP1B) with p-MET and MET, which accounted mainly for THEMIS2-mediated effect on cancer stemness and chemoresistance. Increased THEMIS2 expression was associated with poor survival in TNBC patients and in patients from our breast cancer cohort. We found that non-cytotoxic dosages of cryptotanshinone (CPT) could potently inhibit cancer stemness, chemoresistance and tumorigenicity by suppressing expression of THEMIS2. Notably, stable overexpression of THEMIS2 is associated with enhanced sensitivity toward Capmatinib and CPT treatment. Expression levels of THEMIS2 and p-MET protein were positively correlated in the 465 breast cancer specimens. Our study revealed the novel oncogenic role of THEMIS2 and its underlying mechanism via suppressing PTP1B association with MET and thus leading to its activation. Our findings suggest that THEMIS2 could be a biomarker for MET targeted therapy and also provide a potential clinical application using low dosages of CPT for treatment of THEMIS2 positive TNBC.
三阴性乳腺癌（TNBC）由于缺乏有效的内分泌或靶向治疗、侵袭性和高化疗耐药性，预后较差。癌症干细胞（CSC）被认为在癌症复发和化疗耐药性中起关键作用。THEMIS2 被鉴定为三种三阴性乳腺癌（TNBC）和两种卵巢 CSC 系中唯一共同上调的基因。我们发现 THEMIS2 具有内在的信号支架功能，作为一种新型的癌症干细胞调节因子，可促进多种癌症干性特性，包括球体形成、干性标志物表达、化疗耐药性和低数量癌细胞植入的肿瘤发生。我们首次证明 THEMIS2 通过抑制蛋白酪氨酸磷酸酶 1B（PTP1B）与 p-MET 和 MET 的结合，特异性增强 MET 的激活磷酸化，这主要解释了 THEMIS2 对癌症干性和化疗耐药性的影响。THEMIS2 表达增加与 TNBC 患者和我们乳腺癌队列患者的生存不良相关。我们发现非细胞毒性剂量的隐丹参酮（CPT）通过抑制 THEMIS2 的表达，可强力抑制癌症干性、化疗耐药性和肿瘤发生。值得注意的是，稳定过表达 THEMIS2 与增强对 Capmatinib 和 CPT 治疗的敏感性相关。在 465 个乳腺癌标本中，THEMIS2 和 p-MET 蛋白的表达水平呈正相关。我们的研究揭示了 THEMIS2 通过抑制 PTP1B 与 MET 的结合从而导致其激活的新型致癌作用及其潜在机制。我们的研究结果表明 THEMIS2 可能是 MET 靶向治疗的生物标志物，并为使用低剂量 CPT 治疗 THEMIS2 阳性 TNBC 提供了一种潜在的临床应用。
