DCLK1 integrates induction of TRIB3, EMT, drug resistance and poor prognosis in colorectal cancer
DCLK1 integrates induction of TRIB3, EMT, drug resistance and poor prognosis in colorectal cancer
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DOI：
10.1093/carcin/bgz157
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发表时间：
2020-03-01
期刊：
影响因子：
4.7
通讯作者：
Doki, Yuichiro
中科院分区：
文献类型：
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作者：
Makino, Shunichiro;Takahashi, Hidekazu;Doki, Yuichiro
双皮质素样激酶1（DCLK 1）促进人类结直肠癌（CRC）的肿瘤增殖。为了阐明这种关联的机制和临床相关性，我们使用市售结肠癌细胞系（SW 480、HCT 116、CaCO 2、SW 48和SKCO 1）进行表达分析，并对200例切除的CRC样本进行免疫组织化学分析，以了解其与临床特征的相关性。DCLK 1在SW 480和HCT 116细胞中表达量较高。使用短发夹DCLK 1（shDCLK 1）RNA沉默DCLK 1表达抑制这些细胞系的生长和侵袭能力，这些细胞系显示出进入间充质-上皮转化（MET）的迹象。我们发现DCLK 1表达与Tribbles同源物3（TRIB 3）表达强相关的证据，并且沉默TRIB 3也导致这些细胞中的MET表型。在临床样本中，与DCLK 1低表达的样本相比，DCLK 1高表达与总生存期和无复发生存期方面的不良预后相关（P < 0.0001）。单因素和多因素分析结果提示，DCLK 1在临床结肠癌组织中的高表达与结肠癌患者的预后不良、浸润深度和淋巴结转移有关。DCLK 1的表达与结肠癌的恶性程度相关，并提供了一个潜在的治疗靶点。
Doublecortin-like kinase 1 (DCLK1) promotes tumour proliferation in human colorectal cancer (CRC). To elucidate the mechanism and clinical relevance of this association, we performed expression analysis using commercially available colon carcinoma cell lines (SW480, HCT116, CaCO2, SW48 and SKCO1) and immunohistochemical analysis of 200 resected CRC samples for correlation with clinical features. DCLK1 showed a high level of expression, especially in SW480 and HCT116 cells. Silencing DCLK1 expression using short hairpin DCLK1 (shDCLK1) RNA inhibited the growth and invasion capacities of these cell lines, which showed signs of entering into the mesenchymal-epithelial transition (MET). We found evidence of a strong correlation of DCLK1 expression with that of Tribbles homolog 3 (TRIB3), and silencing TRIB3 also led to the MET phenotype in these cells. In the clinical samples, compared with samples showing low expression of DCLK1, high expression was associated with poor prognosis in terms of overall and recurrence-free survival (P < 0.0001). The results of univariate and multivariate analysis suggested that high expression of DCLK1 in clinical colon cancer samples was tied to poor prognosis, cancer invasion depth and lymph node metastasis. DCLK1 expression correlates with malignant grade of colon cancer and offers a potential treatment target.