CT诊断胃癌壁外血管侵犯与其基因及通路的相关性研究

Gastric cancer is a kind of malignant tumor with high degree of heterogeneity. For locally advanced gastric cancer, contrast-enhanced multiple detector computed tomography (CT) is the routine examination for preoperative risk stratification. Based on the results of our previous studies, we found that the CT imaging feature of extramural venous invasion (EMVI), apart from the conventional tumor (T), lymph node (N) and metastatic (M) categories, had been identified as the independent poor prognostic predictor, as well as the characteristic of highly invasion. By using the Radiogenomic and the Bioformatic methods, we have located the aim circular RNA and pathway (hsa_circ_0083125/VEGFB) which highly expressed in the tissue of EMVI positive patients. In order to investigate the molecular mechanism of the development of this semantic image feature (CT detected EMVI), pathologic identified locally advanced gastric patients will be prospectively enrolled. The CT imaging features (EMVI included), clinical characteristics as well as the histologic tissues will be collected. By using the Real-Time PCR method, the aim circRNA and the target mRNA will be tested in large sample cohort. Based on the progressive events recorded within the 1-year’s follow-up, the performance as the prognostic predictor of EMVI will be prospectively investigated. Then the animal models of gastric cancer will be built. By using the positive and negative verification methods, the circRNA and corresponding pathway associated with CT detected EMVI of gastric cancer will be verified. The mechanism of development of the semantic imaging feature (EMVI) will be clarified in this study, which could provide a non-invasive molecular biomarker of gastric cancer, as well as the potentially therapeutic target.

胃癌具有高度异质。对于局部进展期胃癌，CT是患者术前危险分层的常规检查手段。本团队的前期工作首次证实了除了TNM分期外，CT诊断壁外血管侵犯（EMVI）是局部进展期胃癌患者不良预后的独立预测因子，代表着肿瘤具有高度侵袭性。在此基础上，本团队已利用放射基因组学及生物信息学方法锁定了EMVI这一CT影像语义特征相关的目标基因及其通路（hsa_circ_0083125/VEGFB）。为了进一步探讨EMVI发生发展机制，本团队拟将收集病理证实的局部进展期胃癌患者影像、临床信息及组织样本，对上述目标基因进行大样本验证并前瞻性探讨EMVI对于胃癌患者长期预后的预测作用。然后，我们将建立胃癌原位动物模型，通过慢病毒正反验证的实验方法，证实EMVI与目标基因及其通路的关联性，以阐明CT诊断EMVI这一影像语义特征的分子机制，为胃癌患者提供无创性分子特征及潜在治疗靶点。

胃肠道肿瘤的壁外血管侵犯（Extramural Venous Invasion，EMVI）是重要的大体影像特征，可作为患者术前风险分层及预后的预测指标。然而EMVI的研究多集中在结直肠癌领域，对于胃癌EMVI的发生发展机制尚不清晰。因此本研究基于影像基因组学的思路，首先对局部进展期胃癌患者进行术前CT诊断EMVI这一大体影像特征的积分识别；同时对上述入组患者的冻存组织样本进行环状RNA和转录组测序。进而利用生物信息分析方法，确定和CT诊断EMVI这一影像特征相关的circRNA（hsa_circ_0141001）及其通路。经过原样本的PCR验证后，建立该目标circRNA的稳定沉默胃癌细胞系（MKN74，NCI-87及BGC823），进行细胞功能实验。结果显示沉默该circRNA后，细胞增殖、凋亡、迁移等反映胃癌侵袭性的功能均出现不同程度的下降。接着，利用该目标circRNA的稳定沉默细胞系进行了裸鼠原位胃癌种植瘤模型的制备。通过9.4T 磁共振成像，小鼠胃癌EMVI影像特征得以显示。同时和对照组比较，沉默组胃癌肿块大小和EMVI的检出率均显著低于对照组。.. 此外，在转录组水平，本研究发现与胃癌EMVI相关的mRNA基因标签，能够预测患者的长期生存以及对于免疫治疗的反应，上述结果在公共数据库中完成了外部验证。同时上述mRNA标签中的核心基因的表达情况，亦在多种胃癌细胞系及原样本中得以验证。.. 通过上述结果，本研究从circRNA水平提供了胃癌EMVI发生发展的可能机制并在细胞和动物水平得以验证。为大体影像特征发生机制的研究提供了新的思路，并对于胃癌EMVI这一影像特征作为风险分层指标提供了分子水平的证据。