J BIOL CHEM：转录因子CUTL1在胃癌多药耐药发生发展中起重要作用

近日来自第四军医大学、清华大学的研究人员在新研究中证实：转录因子CUTL1是胃癌耐药性的一个负调控因子。这一研究发现在线发表在12月19日的《生物化学杂志》（JBC）杂志上。

文章的通讯作者是第四军医大学的刘志国（Zhiguo Liu）副教授，其主要从事病毒感染与肿瘤发生、肿瘤的多药耐药的研究。现为美国癌症研究学会会员，国际细胞死亡协会会员，中华肿瘤防治杂志编委，肿瘤研究与临床特约审稿人。

胃癌是最常见的恶性肿瘤之一，其发病率及死亡率居恶性肿瘤第二位，且发病率在国内有逐年上升趋势。早期胃癌多无症状或仅有轻微症状。当临床症状明显时，病变已属晚期。而单纯性手术治疗常难以根治，化疗在综合治疗中发挥了重要作用，因此成为治疗胃癌的主要方法之一。但鉴于多药耐药(multi drug resistance，MDR)对胃癌化疗的影响，相当一部分病例化疗效果不理想。故研究胃癌的多药耐药产生机制对提高胃癌的化疗效果、延长病人的生存期有着重要的意义。

为了更好地了解引起耐药的分子机制，研究人员以往构建出了两种同源的多柔比星（doxorubicin）敏感和耐药胃癌细胞系：SGC7901细胞和SGC7901/ADR细胞。在这篇文章中，研究人员证实了转录因子CUTL1在胃癌多药耐药发生发展中起重要作用。

研究人员证实在多柔比星耐药细胞中CUTL1转录活性显着下降。CUTL1表达减少与人类胃癌组织内在抗药性密切相关，可作为一种不良预后生物标记。功能获得（过表达活性CUTL1）和功能丧失（用CUTL1特异性shRNA抑制）研究证实CUTL1活性增高显着提高了细胞对于药物的敏感性，促进了凋亡。反之，CUTL1表达减少则会显着降低细胞药物敏感性，使得凋亡减少。重要的是，研究人员证实调控CUTL1活性可以改变对于多种药物的敏感性。体内小鼠研究表明过表达活性CUTL1可显着提高癌症组织对于化疗的敏感性，因而抑制癌症生长，而降低CUTL1则可导致化疗耐受。

这些研究结果表明CUTL1活性与耐药性呈负相关，因此其是调节胃癌多药耐药的一个有吸引力的治疗靶点。

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doi: 10.1074/jbc.M112.345942
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Transcription factor CUTL1 is a Negative Regulator of drug resistance in Gastric Cancer

Li T, Wang H, Sun Y, Zhao L, Gang Y, Guo X, Huang R, Yang Z, Pan Y, Wu K, Xu L, Liu Z, Fan D.

Gastric cancer is one of the leading causes for malignancy-related mortality worldwide, and drug resistance hampered the clinical efficacy of chemotherapy. To better understand the molecular mechanism causing drug resistance, we previously established an isogenic pair of doxorubicin-sensitive and -resistant gastric cancer cell lines, SGC7901 and SGC7901/ADR cells. Herein, we investigated how modulation of CUTL1 activity affects the response of gastric cancer to frequently usedchemotherapeutic agents. In the present study, we demonstrated that CUTL1 transcription activity was significantly reduced in doxorubicin-resistant cells. Further, decreased CUTL1 expression was strongly associated with intrinsic drug resistance in human gastric cancer tissues and could be used as a poor prognosis biomarker. Both gain-of-function (by overexpression of active CUTL1) and loss-of-function (by CUTL1 specific shRNA knockdown) studies showed that increased CUTL1 activity significantly enhanced cell sensitivity to drugs and led to increased apoptosis, while decreased CUTL1 expression dramatically reduced cell sensitivity to drugs and thus fewer apoptosis. Importantly, modulation of CUTL1 activity resulted in altered sensitivity to multiple drugs. In vivo mice studies indicated that overexpression of active CUTL1 significantly resulted in increased cancer tissue response to chemotherapy and therefore inhibited growth, while knockdown of CUTL1 conferred resistance to chemotherapy. Taken together, our results strongly indicate that CUTL1 activity is inversely associated with drug resistance and thus an attractive therapeutic target to modulate multidrug resistance in gastric cancer.