小细胞肺癌接受射频消融后周边TZ区域内HIF-1a表达的相关生物学意义

The treatment effect of radiofrequency ablation for lung cancer had caused the extensive concern.Although technique and condition of ablation had been improved such as applying multipolar ablation and widening ablation margin but local recurrence was still common.The local recurrence of small cell lung cancer after ablation was even higher but also the specific mechanism is not clear. Former study found that after ablation transition zone came into being between ablated tissue and the unaffected reference zone.The hypoxic microenvironment of transition zone might be the primary cause for the local recurrence. In pervious study we had found that high expression of hypoxia inducible factor-1a (HIF-1a) occurred in hypoxic condition and promoted the proliferation and angiogenesis potential of small cell lung cancer.Whether HIF-1a involved in regulating the proliferation of small cell lung cancer cells in transition zone and cause the local recurrence or not? Besides these, proliferation, differentiation and apoptosis of type Ⅱ alveolar cell play important roles in the progression of lung tissue repair,then whether HIF-1a expression in transition zone involved in this progression or not? Our study would investigate how the change of HIF-1a expression in transition zone after radiofrequency ablation affect the two biological behaviors: local recurrence of small cell lung cancer and repairing for ablation tissue, then expect to supply even more theoretical basis for the multimodality therapy of small cell lung cancer which was mainly with radiofrequency ablation.

射频消融对肺癌的治疗效果已经引起广泛关注，虽然消融技术条件在不断的改进如采用多极消融及拓宽消融边界，但是肿瘤复发的现象仍很常见，尤其以小细胞肺癌局部复发率更高,而且具体机制也不明确。过去的研究证实消融后正常组织与坏死组织之间形成一过渡区域（TZ区域），此区域内低氧微环境可能是复发的主要原因之一。我们的前期研究发现低氧条件下HIF-1a的表达升高并促进小细胞肺癌细胞增殖及血管生成。TZ区域内HIF-1a是否参与调控小细胞肺癌细胞增殖并引起局部复发？由于肺泡Ⅱ型细胞的增殖分化和凋亡决定消融后肺组织的修复，TZ内HIF-1a表达是否也参与此修复过程？该项目拟体内研究射频消融后TZ区域HIF-1a的表达变化对小细胞肺癌的复发及消融灶的修复两方面生物学行为的影响,旨在为以射频消融为主的小细胞肺癌的综合治疗提供更多的理论依据。

射频消融对肺癌的治疗效果已经引起广泛关注，但是肿瘤复发的现象仍很常见，尤其以小细胞肺癌局部复发率更高,且复发机制尚不明确。本研究中我们通过将小细胞肺癌细胞经裸鼠尾静脉注射构建肺部弥漫性转移瘤模型，然后进行右肺上叶特定区域射频消融处理，结果发现：一 右肺上叶消融灶远端RZ区域内HIF-1α表达水平以及区域内转移瘤增殖活性显著高于右肺下叶RZ区域。但相比之下消融灶周边TZ区域内的HIF-1α表达水平最高，其区域内转移瘤增殖活性最强。HIF-1α特异性抑制剂YC-1作用后，消融灶周边TZ区域和远端RZ区域内转移瘤增殖活性显著受抑制，但是不同的是TZ区域内转移瘤增殖与此区域内血管生成潜能无明显关系。二 关于消融灶周边TZ区域内HIF-1α异常高表达的分子机制，课题组发现消融周边区域内残存的肺癌细胞在射频热效应的作用下产生热耐受现象而形成热耐受亚型，54˚C培养下产生的肺癌细胞热耐受亚型增殖活性最强，随着培养温度进一步升高，产生的肺癌细胞热耐受亚型增殖活性有所降低，但都强于亲代肺癌细胞。肺癌细胞热耐受亚型的增殖活性与HIF-1α表达密切相关，而HIF-1α表达受HSP70直接调控，PI3K/Akt以及MAPK/ERK信号通路均参与HSP70/HIF-1α表达的调控过程。三 课题组还发现除了残存的肺癌细胞，肺泡Ⅱ型细胞也射频消融热效应的作用下产生热耐受形成热耐受亚型，其HIF-1α表达显著高于亲代细胞。抑制HIF-1α表达能明显促进肺泡Ⅱ型细胞热耐受亚型增殖活性并促进肺组织修复过程。总结：本研究证实了射频消融后TZ区域HIF-1α高表达能够诱导局部区域复发并抑制肺组织再生修复，而HIF-1α高表达是射频消融热刺激及HSP70诱导作用的结果，因此针对HIF-1α的靶向治疗作为术后辅助治疗对于提高肺癌射频消融治疗效果有着重要的意义，因此本课题旨在为以射频消融为主的肺癌包括小细胞肺癌的综合治疗提供更多的理论依据。

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