SIP1 induced epithelial to mesenchymal transition (EMT) promotes metastasis and chemoresistance in colorectal cancer.

SIP1 诱导上皮间质转化 (EMT) 促进结直肠癌的转移和化疗耐药。

• 批准号: MR/L017539/1
• 负责人: Rahul Sreekumar
• 金额: $ 26.11万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL017539%2F1
• 关键词: SIP1; induced; epithelial; mesenchymal; transition

Bowel cancer is the second most common cause of cancer related death in the UK, and it is spread of the cancer (Metastasis), that is the main cause of this high death rate. Unfortunately, up to a third of patients present with evidence of cancer spread at initial presentation, and up to half of all cases subsequently experience recurrence of disease from previously undetected occult metastases after their operation. While there has been some advances in the management of patients with recurrent bowel cancer, the vast majority of patients in this position are incurable and sadly can expect a median life expectancy of less than two years, even with the latest chemotherapy drugs. Emerging evidence in recent years has highlighted the role of certain key molecules that normally regulate the development of embryos, to be abnormally expressed in cancer cells, making them not only more likely to invade and spread, but also to become resistant to chemotherapeutic drugs. Little is known about the expression or role of one of these key proteins, known as SIP1, in bowel cancer. Preliminary work conducted by me so far has highlighted that SIP1, when present in bowel tumors, results in an increased likelihood of cancer recurrence, reduced patient survival, and increased resistance against commonly used chemotherapeutic drugs in the treatment of bowel cancer. Consequently, SIP1 may be a helpful biomarker for clinically useful outcome measures in patients with bowel cancer. I have conducted further work to try to explain the mechanism behind this observation. Our results suggested that one potential explanation for the resistance to chemotherapy observed is due to the increased ability of cancer cells, containing SIP1, to repair the damage brought about by chemotherapy, and thereby avoid cancer cell death. Based on the above novel observations, the primary goals of my research proposal are two fold. The first aim of my study is to better understand the underlying mechanisms by which bowel cancer cells increase their capacity to repair cellular injury through the actions of SIP1. This work will not only enhance our understanding of basic biological processes in cells, but it may also enable the creation of targeted drugs to inhibit these repair systems and subsequently increase the sensitivity of cancer cells to chemotherapy drugs, potentially impacting the lives of many sufferers. This work will involve the use of cells grown in culture, but also studies in a carefully calculated number of mice to ensure that my findings are as closely related to physiological circumstances as possible, and therefore more likely to take the next step and enter studies in man.As a clinician, my goal is to translate new laboratory findings into patient care, consequently my second aim is to more fully develop and test the use of SIP1 as a biomarker that could help in the personalisation of the management of bowel cancer by assisting in risk prediction for cancer recurrence and potentially chemotherapy response. Validating my promising results on a larger and independent group of patients is an essential per-requisite for translating these findings into real-time patient management. For that reason, I have teamed up with colleagues in Italy and we aim to test the generality of my findings in an independent patient group from their unit. If successful, my research will provide significant insight into mechanisms by which cancer spreads and gains resistance to current drug therapies, and may facilitate better clinical management and drug discovery in future years.

在英国，肠癌是癌症相关死亡的第二大常见原因，而癌症的扩散（转移）是导致高死亡率的主要原因。不幸的是，多达三分之一的患者在最初就诊时就有癌症扩散的迹象，而在所有病例中，多达一半的患者在手术后因以前未发现的隐匿转移而复发。虽然在治疗复发性肠癌患者方面已经取得了一些进展，但绝大多数这种情况的患者是无法治愈的，可悲的是，即使使用最新的化疗药物，患者的平均预期寿命也不到两年。近年来出现的新证据强调了正常情况下调节胚胎发育的某些关键分子在癌细胞中异常表达的作用，这不仅使它们更容易入侵和扩散，而且还使它们对化疗药物产生耐药性。人们对其中一种被称为SIP1的关键蛋白在肠癌中的表达或作用知之甚少。到目前为止，我所做的初步工作已经强调，当SIP1存在于肠道肿瘤中时，会导致癌症复发的可能性增加，患者生存期降低，并且增加对肠癌治疗中常用化疗药物的耐药性。因此，SIP1可能是一种有用的生物标志物，可用于肠癌患者的临床预后测量。我已经进行了进一步的研究，试图解释这一观察结果背后的机制。我们的研究结果表明，对观察到的化疗耐药性的一个潜在解释是由于含有SIP1的癌细胞修复化疗带来的损伤的能力增强，从而避免癌细胞死亡。基于上述新颖的观察，我的研究计划的主要目标是两个方面。我的研究的第一个目的是更好地了解肠癌细胞通过SIP1的作用增加其修复细胞损伤的能力的潜在机制。这项工作不仅将增强我们对细胞中基本生物过程的理解，而且还可能使我们能够创造出靶向药物来抑制这些修复系统，并随后增加癌细胞对化疗药物的敏感性，这可能会影响许多患者的生活。这项工作将涉及使用培养细胞，但也会在精心计算的小鼠数量中进行研究，以确保我的发现尽可能与生理环境密切相关，因此更有可能采取下一步并进入人体研究。作为一名临床医生，我的目标是将新的实验室发现转化为患者护理，因此我的第二个目标是更充分地开发和测试SIP1作为一种生物标志物的使用，通过协助癌症复发和潜在化疗反应的风险预测，有助于肠癌管理的个性化。在更大的独立患者群体中验证我的有希望的结果是将这些发现转化为实时患者管理的必要条件。出于这个原因，我与意大利的同事合作，我们的目标是在他们单位的一个独立患者群体中测试我的发现的普遍性。如果成功，我的研究将为癌症扩散和对当前药物治疗产生耐药性的机制提供重要的见解，并可能在未来几年促进更好的临床管理和药物发现。

项目成果

Can ZEB2 Be Used as a Molecular Marker for Risk Stratification of Patients With Colorectal Cancer?

ZEB2可以作为结直肠癌患者风险分层的分子标志物吗？

• DOI: 10.1001/jamanetworkopen.2018.3133
• 发表时间: 2018
• 期刊: JAMA Network Open
• 影响因子: 13.8
• 作者: Vu J

The ZEB2-dependent EMT transcriptional programme drives therapy resistance by activating nucleotide excision repair genes ERCC1 and ERCC4 in colorectal cancer.

• DOI: 10.1002/1878-0261.12965
• 发表时间: 2021-08
• 期刊: Molecular oncology
• 影响因子: 6.6
• 作者: Sreekumar R;Al-Saihati H;Emaduddin M;Moutasim K;Mellone M;Patel A;Kilic S;Cetin M;Erdemir S;Navio MS;Lopez MA;Curtis N;Yagci T;Primrose JN;Price BD;Berx G;Thomas GJ;Tulchinsky E;Mirnezami A;Sayan AE
• 通讯作者: Sayan AE