长链非编码RNA HOXA末端转录本反义RNA对胰腺癌诊断的临床价值

Clinical value of long non-coding RNA HOXA terminal transcript antisense RNA in the diagnosis of pancreatic cancer

目的探讨长链非编码RNA(lncRNA)HOXA末端转录本反义RNA(HOTTIP)对胰腺癌诊断的临床价值。方法收集2017年6月至2018年12月间徐州市中心医院18例行手术切除并经病理证实的胰腺癌组织及癌旁正常胰腺组织(距癌组织>1 cm);收集78例临床确诊的胰腺癌患者血浆,选取78例健康体检者作为健康对照组,同时收集原发性肝癌、结直肠癌及胃癌各50例作为疾病对照组。实时荧光定量PCR法检测胰腺癌组组织及血浆、健康对照组和疾病对照组血浆HOTTIP的表达水平,化学发光法检测胰腺癌患者血浆CA19-9水平。分析胰腺癌患者血浆HOTTIP与癌组织HOTTIP及血浆CA19-9相关性,分析血浆HOTTIP水平与肿瘤临床病理特征之间的关系。绘制高表达HOTTIP组和低表达HOTTIP组患者的生存曲线,log-rank检验比较两组间的生存率差异。绘制受试者工作特征曲线(ROC),计算曲线下面积(AUC),评估血浆HOTTIP水平对胰腺癌的诊断效能。结果胰腺癌患者癌组织HOTTIP表达量显著高于癌旁正常胰腺组织(2.24±0.25比0.62±0.11,P<0.001);胰腺癌、肝癌、结直肠癌、胃癌患者及健康对照者血浆HOTTIP水平分别为1.33±0.32、0.57±0.17、0.51±0.10、0.41±0.09、0.54±0.05,胰腺癌组显著高于肝癌、结直肠癌、胃癌患者及健康对照者,差异均有统计学意义(P值均<0.05),但肝癌、结直肠癌、胃癌患者血浆HOTTIP水平与健康对照者的差异均无统计学意义。胰腺癌患者血浆HOTTIP表达与CA19-9及癌组织中HOTTIP表达均呈正相关(P值均<0.001),且血浆HOTTIP表达水平与TNM分期有关(P=0.029),而与患者性别、年龄及淋巴结转移、肿瘤大小无关。HOTTIP高表达患者生存率明显低于HOTTIP低表达患者(15.9个月比30.6个月,P<0.05)。血浆HOTTIP水平诊断胰腺癌的AUC值为0.81(95%CI 0.74~0.87),诊断临界值为1.14,灵敏度为62%,特异度为94%,准确性为74%。血浆HOTTIP联合CA19-9诊断胰腺癌的灵敏度提高到81%,特异度提高到97%,准确性提高到84%。结论胰腺癌患者血浆HOTTIP水平对胰腺癌的诊断具有一定的临床价值。

Objective To investigate the clinical value of the long non-coding RNA HOXA terminal transcript antisense RNA(HOTTIP)for diagnosing pancreatic cancer(PC).Methods PC tissue and adjacent normal tissue(>1 cm distant from cancer tissue)from 18 PC patients confirmed by pathology after surgery were collected from June 2017 to December 2018 in Xuzhou Central Hospital.Plasma samples from 78 PC patients clinically confirmed were collected,those from 78 healthy individuals were designed as healthy controls and those from 50 patients of liver cancer,50 patients of colorectal cancer and 50 patients of gastric cancer were also collected as disease controls.HOTTIP expression in PC tissue and plasma of PC patients,disease controls and healthy controls was tested by real time quantitative polymerase chain reaction;the plasma CA19-9 level was tested by CLIA.The correlation between plasma HOTTIP,cancer tissue HOTTIP and plasma CA19-9 were analyzed,and the relationship between plasma HOTTIP and clinicopathological features was analyzed.The survival curves of patients with high and low expression of HOTTIP were drawn,and the difference of survival rates between the two groups was compared by log-rank test.Receiver operating characteristic(ROC)curves were drawn to calculate area under the ROC curve(AUC),and the diagnostic performance of plasma HOTTIP for PC was evaluated.Results Compared to normal pancreatic tissue,the level of HOTTIP expression was significantly up-regulated in pancreatic cancer tissue(2.24±0.25 vs 0.62±0.11,P<0.001),the relative expression of plasma HOTTIP of PC,liver cancer,colorectal cancer,gastric cancer patients and healthy controls were 1.33±0.32,0.57±0.17,0.51±0.10,0.41±0.09 and 0.54±0.05;HOTTIP level of PC patients was higher than that of liver cancer,colorectal cancer,gastric cancer patients and healthy controls(all P<0.05),but the difference on HOTTIP level between liver cancer,colorectal cancer,gastric cancer patients and healthy controls was not statistically significant.The plasma HOTTIP of PC patients had a strong positive correlation with plasma CA19-9 and also had a positive correlation with HOTTIP level in cancer tissue(all P<0.05);meanwhile the plasma level of HOTTIP was significantly correlated with TNM stage(P=0.029),but not with sex,age,lymph node metastasis and tumor size.The median survival time of patients with high HOTTIP level was obviously lower than that of those with low HOTTIP level(15.9 months vs 30.6 months,P<0.05).The AUC of plasma HOTTIP for diagnosing PC was 0.81(95%CI 0.74-0.87).At the optimal cutoff value of 1.14,the diagnostic sensitivity,specificity and accuracy were 62%,94%and 74%.By combining plasma HOTTIP with CA19-9,the diagnostic sensitivity,specificity and accuracy can be increased to 81%,97%and 84%,respectively.Conclusions Plasma HOTTIP level has a significant value in the diagnosis of PC.