Chemotherapy Resistance in Diffuse-Type Gastric Adenocarcinoma Is Mediated by RhoA Activation in Cancer Stem-Like Cells.
Chemotherapy Resistance in Diffuse-Type Gastric Adenocarcinoma Is Mediated by RhoA Activation in Cancer Stem-Like Cells.
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DOI：
10.1158/1078-0432.ccr-15-1356
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发表时间：
2016-02-15
期刊：
影响因子：
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通讯作者：
Yoon SS
中科院分区：
文献类型：
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作者：
Yoon C;Cho SJ;Aksoy BA;Park DJ;Schultz N;Ryeom SW;Yoon SS
Lauren弥漫性胃腺癌（DGA）与肠型胃腺癌（IGA）不同，常发生RHOA突变，但RHOA在DGA中的作用尚不清楚。我们在DGA细胞系和两种小鼠异种移植模型中检测了RhoA活性和RhoA通路抑制。还评估了患者肿瘤样本中的RhoA活性。与IGA细胞系相比，DGA细胞系中的RhoA活性更高，当作为球形细胞培养以富集癌症干细胞样细胞（CSC）或使用胃CSC标记物CD44进行分类时，RhoA活性进一步提高。RhoA shRNA或RhoA抑制剂Rhosin降低了干细胞转录因子Sox2的表达，使球状体的形成减少了78-81%。DGA球形细胞的迁移和侵袭能力是单层细胞的3-5倍，并且这种活性依赖于rho。在细胞毒性试验中，弥漫性GA球形细胞对5-氟尿嘧啶和顺铂化疗具有耐药性，这种耐药性可以通过抑制RhoA途径逆转。在两种异种移植模型中，顺铂抑制肿瘤生长40-50%，抑制RhoA 32-60%，联合抑制77-83%。在288例肿瘤患者中，DGA患者的RhoA活性升高与较差的OS相关（p=0.017），而IGA患者的RhoA活性升高与较差的OS相关（p=0.612）。RhoA信号传导促进DGA细胞的CSC表型。RhoA活性升高与DGA患者的OS恶化相关，RhoA抑制可以逆转DGA CSC和肿瘤异种移植物的化疗耐药。因此，RhoA通路是DGA患者一个有希望的新靶点。
The Lauren diffuse type of gastric adenocarcinoma (DGA), as opposed to the intestinal type (IGA), often harbor mutations in RHOA but little is known about the role of RhoA in DGA. We examined RhoA activity and RhoA pathway inhibition in DGA cell lines and in two mouse xenograft models. RhoA activity was also assessed in patient tumor samples. RhoA activity was higher in DGA compared to IGA cell lines, and was further increased when grown as spheroids to enrich for cancer stem-like cells (CSC) or when sorted using the gastric CSC marker CD44. RhoA shRNA or the RhoA inhibitor Rhosin decreased expression of the stem cell transcription factor, Sox2, and decreased spheroid formation by 78–81%. DGA spheroid cells had 3–5 fold greater migration and invasion than monolayer cells, and this activity was Rho-dependent. Diffuse GA spheroid cells were resistant in a cytotoxicity assay to 5-fluorouracil and cisplatin chemotherapy, and this resistance could be reversed with RhoA pathway inhibition. In two xenograft models, cisplatin inhibited tumor growth by 40–50%, RhoA inhibition by 32–60%, and the combination by 77–83%. In 288 patient tumors, increased RhoA activity correlated with worse OS in DGA patients (p=0.017) but not in IGA patients (p=0.612). RhoA signaling promotes CSC phenotypes in DGA cells. Increased RhoA activity is correlated with worse OS in DGA patients and RhoA inhibition can reverse chemotherapy resistance in DGA CSC and in tumor xenografts. Thus the RhoA pathway is a promising new target in DGA patients.