背景:胆道癌(BTC)是一种相对罕见但侵袭性的胃肠道癌症,死亡率很高。癌症干细胞(CSC)群体在肿瘤生物学中起着至关重要的作用,并且是对抗癌治疗反应低和复发率高的原因。这项研究调查了Transgelin-2(TAGLN2)的作用,在BTC细胞中CSC过表达,并分析其在患者组织和血清中的表达,以确定BTC的潜在新靶标。
方法:TAGLN2表达被小干扰或短发夹RNA抑制,在几种BTC细胞系中评估了其对肿瘤生物学的影响。此外,TAGLN2沉默对吉西他滨耐药BTC细胞的影响,差异表达基因,蛋白质,和对治疗或辐射的敏感性进行了评估。还使用从BTC患者获得的样品中的蛋白质印迹和免疫组织化学来评估TAGLN2表达,以验证其临床应用。
结果:抑制BTC细胞系中的TAGLN2降低了细胞增殖,迁移,入侵,和肿瘤大小,除了CSC功能的减少,包括克隆性,抗辐射性,和化学抗性。TAGLN2在BTC组织中高表达,特别是在基质中与癌症相关的成纤维细胞中。与基质免疫组织化学指数高的患者相比,基质免疫组织化学指数低的患者无病生存期延长(11.5vs.7.4个月,P=0.013)。BTC患者血浆中TAGLN2的表达高于良性疾病患者。TAGLN2的曲线下面积(0.901)高于CA19-9,这是一种有效的肿瘤生物标志物(0.799;P<0.001)。
结论:TAGLN2在促进BTC细胞生长和运动中起关键作用,并参与调节BTC的干性。沉默TAGLN2表达增强细胞对放射和化疗药物的敏感性。TAGLN2在患者组织和血浆中的表达表明其作为BTC的分泌性生物标志物的潜力。总的来说,靶向TAGLN2可能是化疗失败后针对晚期癌症的合适治疗策略.
BACKGROUND: Biliary tract cancer (BTC) is a relatively rare but aggressive gastrointestinal cancer with a high mortality rate. Cancer stem cell (CSC) populations play crucial roles in tumor biology and are responsible for the low response to anti-cancer treatment and the high recurrence rate. This study investigated the role of Transgelin-2 (TAGLN2), overexpressed in CSC in BTC cells, and analyzed its expression in patient tissues and serum to identify potential new targets for BTC.
METHODS: TAGLN2 expression was suppressed by small-interfering or short hairpin RNAs, and its effects on tumor biology were assessed in several BTC cell lines. Furthermore, the effects of TAGLN2 silencing on gemcitabine-resistant BTC cells, differentially expressed genes, proteins, and sensitivity to therapeutics or radiation were assessed. TAGLN2 expression was also assessed using western blotting and immunohistochemistry in samples obtained from patients with BTC to validate its clinical application.
RESULTS: Suppression of TAGLN2 in BTC cell lines decreased cell proliferation, migration, invasion, and tumor size, in addition to a reduction in CSC features, including clonogenicity, radioresistance, and chemoresistance. TAGLN2 was highly expressed in BTC tissues, especially in cancer-associated fibroblasts in the stroma. Patients with a low stromal immunohistochemical index had prolonged disease-free survival compared to those with a high stromal immunohistochemical index (11.5 vs. 7.4 months, P = 0.013). TAGLN2 expression was higher in the plasma of patients with BTC than that in those with benign diseases. TAGLN2 had a higher area under the curve (0.901) than CA19-9, a validated tumor biomarker (0.799; P < 0.001).
CONCLUSIONS: TAGLN2 plays a critical role in promoting BTC cell growth and motility and is involved in regulating BTC stemness. Silencing TAGLN2 expression enhanced cell sensitivity to radiation and chemotherapeutic drugs. The expression of TAGLN2 in patient tissue and plasma suggests its potential to serve as a secretory biomarker for BTC. Overall, targeting TAGLN2 could be an appropriate therapeutic strategy against advanced cancer following chemotherapy failure.