RelB转录调控去乙酰化酶SIRT3诱导前列腺癌放疗抵抗的分子机制研究

Radioresistence is one of the main factors which affect curative effect in prostate cancer. It is very meaningful to clarify the molecular mechanisms of radioresistence. Recent studies have demonstrated that RelB, the transcription factor of the noncanonical NF-κB pathway, is correlated with the radioresistance of prostate cancer, but the detailed mechanisms remain elusive. Our previous studies first demonstrated that RelB may transcriptionally regulate deacetylase SIRT3 in response to oxidative stress and DNA damage repair. Moreover, it was found that NBS1, a key DNA damage repair protein, might be a potential substrate of SIRT3. Thus, we hypothesize that RelB may induce radioresistence in prostate cancer by transcriptionally regulating SIRT3 which inhibits oxidative stress and promotes DNA damage repair. The study intents to verify the key role of RelB-SIRT3 signal pathway in prostate cancer radioresistence both in vitro and in vivo, then demonstrates the mechanisms of RelB in prostate cancer radioresistence by transcriptionally regulating SIRT3, then activating downstream substrates of SIRT3 which inhibit oxidative stress and enhance DNA damage repair. Finally, the study also tries to evaluate whether RelB expression is correlated with the radiotherapeutic effects and prognosis in clinical settings. This work will provide laboratory evidences for radiosensitive marker seeking and individualized treatments of prostate cancer in future.

放疗抵抗是影响前列腺癌临床整体疗效的主要因素之一，阐明其分子机制意义重大。NF-κB非经典通路转录因子RelB与前列腺癌放疗抵抗密切相关，但分子机制未明。我们前期工作首次发现RelB可能通过转录调控去乙酰化酶SIRT3参与氧化应激反应及DNA损伤修复，并发现DNA损伤修复关键蛋白NBS1可能是SIRT3潜在底物。我们由此推测RelB可能通过转录调控SIRT3抑制细胞氧化应激、促进DNA损伤修复诱导前列腺癌放疗抵抗。本研究拟通过体内及体外实验明确RelB-SIRT3信号通路诱导前列腺癌放疗抵抗的关键作用，进一步在分子水平揭示RelB转录调控SIRT3并激活SIRT3下游底物抑制细胞氧化应激、促进DNA损伤修复诱导前列腺癌放疗抵抗的分子机制，最后从临床角度探索RelB与前列腺癌放疗疗效及预后的关联，为未来寻找前列腺癌放疗增敏靶点及个体化治疗提供实验依据。

放射治疗在肿瘤治疗中起到至关重要的作用。然而肿瘤细胞对放射线的固有抵抗及适应性耐受会直接影响临床疗效。目前，肿瘤放疗抵抗的机制仍不清晰，预测及克服放疗抵抗的手段匮乏，是临床及转化研究中严峻的挑战。因此，探索放疗抵抗机制对肿瘤放疗基础研究和临床治疗新技术开发十分重要。本课题组在前期研究基础上，深入探索了肿瘤放疗抵抗的功能机制。我们首先利用临床样本及公共数据库阐述NF-κB非经典通路因子RelB诱导前列腺放疗抵抗的临床意义，并通过对RelB-SIRT3信号通路的精细研究，明确了RelB调控氧化应激与DNA损伤修复参与前列腺癌放疗抵抗的潜在机制。随后，我们探索了肿瘤微环境中基质细胞对放疗抵抗的影响。研究显示前列腺癌基质细胞可大量分泌IL-8，并利用外泌体传递给肿瘤细胞，激活AMPK信号通路促进肿瘤进展和放射抵抗。在结直肠癌中，我们成功构建具有天然放化疗抗性的肿瘤再生细胞（tumor repopulating cells, TRCs）模型，并从中发现F-肌动蛋白调节因子KIAA1211参与结直肠癌干性形成和恶性进展的内在机制。下调KIAA1211可导致YAP滞留在细胞质中，促进干细胞标记物NANOG和OCT4表达，同时促进结直肠癌细胞软化并调节EMT状态，最终提高其转移潜能。KIAA1211在放疗抵抗中的作用正在进一步研究。另一部分的研究发现RelB可能通过调控铁死亡参与直肠癌放疗抵抗，初步研究显示铁死亡抑制蛋白1（ferroptosis suppressor protein 1，FSP1）是RelB潜在下游靶点。我们的研究从肿瘤微环境、肿瘤干性、氧化应激等多角度探索了肿瘤恶性进展及放疗抵抗的内在机制，为临床疗效预测、新型靶标及放疗增敏药物的研发提供科学依据。