Qiu Shimei, Liu Zhaonan, Hu Jun, Wang Ziyi, Yue Zhuying, Jia Ziheng, Zhang Wenhua, Xue Ziru, Liu Zebing, Liu Yingbin
School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China.
Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
Int J Med Sci. 2024 Mar 25;21(5):862-873. doi: 10.7150/ijms.93413. eCollection 2024.
Direct liver invasion (DI) is a predominant pathway of gallbladder cancer (GBC) metastasis, but the molecular alterations associated with DI remain addressed. This study identified specific genes correlated with DI, which may offer a potential biomarker for the diagnosis and prognosis of advanced GBC. RNA samples from 3 patients with DI of GBC were used for RNA-seq analysis. Differentially expressed genes and metabolic pathways between primary tumor (T) and DI tissue was used to analyze aberrant gene expressions. Immunohistochemistry (IHC) of fatty acid binding protein 1 (FABP1) in 62 patients with DI was engaged to evaluate its association with clinicopathological characteristics and prognosis. IHC of CD3 and CD8 T cells was analyzed for their correlation with FABP1 expression, clinicopathological features and prognosis. Univariate and multivariate Cox hazards regression analyses were performed to identify independent prognostic factors for disease-free survival (DFS) and overall survival (OS). FABP1 mRNA levels were significantly upregulated in DI region compared to T tissue. IHC results showed identical results with elevated FABP1 (p < 0.0001). Expression of FABP1 in DI region was significantly associated with lymph node metastasis (P = 0.028), reduced DFS (P = 0.013) and OS (P = 0.022); in contrast, its expression in T region was not associated with clinicopathological characteristics and prognosis (P > 0.05). The density of CD8 T cells in DI region with higher FABP1 expression was significantly lower than that with lower FABP1 expression (p = 0.0084). Multivariate analysis unveiled those hepatic metastatic nodules (HR = 3.35, 95%CI: 1.37-8.15, P = 0.008) and FABP1 expression in DI region (HR = 2.01, 95%CI: 1.05-3.88, P = 0.036) were high risk factors for OS, and FABP1(HR = 2.05, 95%CI: 1.04-4.06, P = 0.039) was also a high risk factor for DFS. Elevated expression of FABP1 in DI region serves as a potential prognostic biomarker for advanced GBC with DI.
肝脏直接侵犯（DI）是胆囊癌（GBC）转移的主要途径，但与DI相关的分子改变仍未得到解决。本研究确定了与DI相关的特定基因，这可能为晚期GBC的诊断和预后提供潜在的生物标志物。来自3例GBC发生DI的患者的RNA样本用于RNA测序分析。利用原发性肿瘤（T）和DI组织之间差异表达的基因和代谢途径来分析异常基因表达。对62例发生DI的患者进行脂肪酸结合蛋白1（FABP1）的免疫组织化学（IHC）检测，以评估其与临床病理特征和预后的关系。分析CD3和CD8 T细胞的IHC结果与FABP1表达、临床病理特征和预后的相关性。进行单因素和多因素Cox风险回归分析，以确定无病生存期（DFS）和总生存期（OS）的独立预后因素。与T组织相比，DI区域的FABP1 mRNA水平显著上调。IHC结果显示FABP1升高的结果相同（p<0.0001）。DI区域FABP1的表达与淋巴结转移（P=0.028）、DFS降低（P=0.013）和OS降低（P=0.022）显著相关；相反，其在T区域的表达与临床病理特征和预后无关（P>0.05）。FABP1表达较高的DI区域中CD8 T细胞的密度显著低于FABP1表达较低的区域（p=0.0084）。多因素分析显示，肝转移结节（HR=3.35，95%CI：1.37-8.15，P=0.008）和DI区域FABP1表达（HR=2.01，95%CI：1.05-3.88，P=0.036）是OS的高危因素，FABP1（HR=2.05，95%CI：1.04-4.06，P=0.039）也是DFS的高危因素。DI区域FABP1表达升高是发生DI的晚期GBC的潜在预后生物标志物。
