TIAM1 promotes chemoresistance and tumor invasiveness in colorectal cancer
TIAM1 promotes chemoresistance and tumor invasiveness in colorectal cancer
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DOI：
10.1038/s41419-019-1493-5
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发表时间：
2019-03-19
影响因子：
9
通讯作者：
Goel, Ajay
中科院分区：
文献类型：
--
作者：
Izumi, Daisuke;Toden, Shusuke;Goel, Ajay
越来越多的证据表明，具有干细胞样特征的癌细胞对化疗药物具有更高的抗性。在此，我们鉴定了T淋巴瘤侵袭和转移诱导蛋白-1（TIAM 1）作为驱动自我更新的Wnt信号传导相关基因之一，并且其表达被癌症相关成纤维细胞（CAF）上调。在300例对化疗有反应或无反应的患者的结直肠癌（CRC）切除组织中评估了TIAM 1表达。使用siRNA和CRISPR/Cas9来检查TIAM 1的抑制是否影响CRC的化学敏感性。我们证明，通过Wnt信号调节化疗敏感性的干细胞，这种现象只发生在癌症干细胞。随后，我们建立了患者来源的CAF，并测试了CRC细胞系的药物敏感性是否被CAF来源的条件培养基改变。TIAM 1高表达与结直肠癌患者的不良预后显著相关，并且在对化疗无反应的患者中过表达。我们在一系列体外实验中证明了TIAM 1的抑制增强了对化疗药物的敏感性并降低了肿瘤的侵袭性。此外，CAF衍生的条件培养基通过TIAM 1过表达增加了CRC细胞系的干细胞性和化学抗性。此外，我们使用异种移植模型验证了TIAM 1相关的药物敏感性。我们已经证明，TIAM 1在对化疗药物无反应的患者的CRC肿瘤中过表达，TIAM 1表达水平可作为独立的预后因素。从机制上讲，CAF通过TIAM 1过表达增强CRC化疗耐药性。总的来说，这些结果表明TIAM 1调节肿瘤和间质的化学敏感性，因此可能是一个有吸引力的治疗靶点。
Accumulating evidence suggests that cancer cells with stem cell-like features have higher resistance to chemotherapeutic agents. Herein, we identified T-lymphoma invasion and metastasis-inducing protein-1 (TIAM1) as one of the Wnt-signaling associated genes which drives self-renewal and its expression is upregulated by cancer associated fibroblasts (CAFs). TIAM1 expression was assessed in resected colorectal cancer (CRC) tissues from 300 patients who did or did not respond to chemotherapy. siRNA and CRISPR/Cas9 was used to examine whether the inhibition of TIAM1 affects chemosensitivity of CRC. We demonstrate that stemness through Wnt signaling regulates chemosensitivity and this phenomenon occurs exclusively in cancer stem cells. Subsequently, we established patient-derived CAFs and tested whether the drug sensitivity of CRC cell lines is altered with CAF-derived conditioned medium. High-TIAM1 expression correlated significantly with poor prognosis of CRC patients, and was overexpressed in patients who did not respond to chemotherapy. We demonstrated that the inhibition of TIAM1 enhanced sensitivity to chemotherapeutic drugs and reduced tumor invasiveness in a series of experiments in vitro. Moreover, CAF-derived conditioned media increased stemness and chemoresistance in CRC cell lines through TIAM1 overexpression. In addition, we validated TIAM1 associated drug sensitivity using a xenograft model. We have demonstrated that TIAM1 is overexpressed in CRC tumors from patients who did not respond to chemotherapeutic drugs and levels of TIAM1 expression served as an independent prognostic factor. Mechanistically, CAFs enhanced CRC chemoresistance through TIAM1 overexpression. Collectively, these results suggest that TIAM1 regulates chemosensitivity in tumors and stroma and thus may be an attractive therapeutic target.