| BackgroundHepatocellular carcinoma(HCC), the most common primary liver cancer, is the fifth most frequent cancer and the third cause of cancer-related mortality worldwide. An estimated 782,500 new liver cancer cases and 745,500 cancer deaths occurred worldwide during 2012. Half of these cases and deaths were estimated to occur in China. Most patients with HCC are diagnosed at the intermediate to advanced stages, so that only 30% of patients with HCC are eligible to receive surgery. When surgical options are precluded, transarterial chemoembolization (TACE) is one of the options that can be used to treat locally advanced tumors in the liver. At present, TACE treatment is the main therapy in China, accounted for 61.9% of the advanced HCC patients. The short term thepary efficacy of TACE treatment is not bad, but several studies demonstrated that the long term therapy efficacy was not satisfying with the high retention rate about 90%. since the formation of anaerobic environment results in the formation of the new tumor vessels, the probability of tumor recurrence and metastasis increase, which will shorten the overall survival of the HCC patients. Hence, it is vital to explore a sensitive and specific tumor biomarker to predict the treatment response and the recurrence probablity based on the hypoxia after the TACE treatment.Recent years, miRNAs had been had the potential contribution to the tumor early diagnosis and treatment response prediction. miRNAs are small noncoding RNAs about 19 to 25 nucleotides long which mainly function in posttranscriptional gene regulation. During the regulation process, miRNAs can pair to complementary binding sites within the 3’ untranslated region of any of hundreds of target mRNAs, and as a result, they participate in nearly all biological processes with conservatism and endogenous. It has been reported that miRNAs exist in serum or plasm.Most previous studies on miRNA expression have been performed on tissue samples. However, recent findings have demonstrated that human serum and plasma contain a large number of stable miRNAs, and that the expression profile of these miRNAs holds great promise as a novel noninvasive biomarker, because tumor-derived miRNAs can be present and exist stably in blood. The blood contains vesicles released from cells. Those vesicles contain miRNAs. There are positive correlations between miRNA expression levels in the vesicles and those in cells. Circulating miRNAs are highly stable in the serum. They are resistant to RNase activity, extreme pH, and temperature. High serum stability allows miRNAs to act as biomarkers for cancers, including HCC.In fact, serum miRNAs have been intensively studied as potential biomarkers for use in the diagnosis of HCC.This research has innovation to associate the HCC specific miR-199a/b-3p with the most applied TACE treatment in HCC patients in order to explore the HCC miR-199a/b-3p expression regular, the influence of TACE treatment and the relationship with TACE treatment response. We hope wether serum miR-199a/b-3p has the potential role to be a satisfying tumor biomarker. The early prediction of TACE treatment response contributes to the individualized treatment of HCC patients and overall survival.PurposeTo investigate whether the level of serum microRNA-199a/b-3p (miR-199a/b-3p) can serve as a predictor of treatment response to transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC).Materials and MethodsIn total 132 patients with unresectable HCC who underwent TACE for the first time at our hospital, between March 2014 and October 2014, were enrolled into the present study. Aged 57.1±10.3 (38-72) years old, male about 80%. The average tumor size was 7.1cm, ranged from 2.2 to 15.7 cm.132 HCC patients were treated with TACE as the first treatment towards the tumor, and among them 126 HCC patients was treated with TACE after the first TACE, with 6 HCC patients lossed follow up. Serum levels of a-fetoprotein (AFP) (≥400ng/mL) were elevated in 48%. Most patients had a Child-Pugh A classification (77%), and multiple liver tumor lesions (66%). According to the Barcelona Clinic Liver Cancer (BCLC) staging system,36 patients (27%) had stage A,60 (45%) had stage B, and 36 (27%) had stage C tumors.The healthy controls were 50 normal persons, including 25 person without HBV positive, cirrhosis and 25 portal hypertension patients with HBV positive, cirrhosis. Inclusion criteria of HCC patients including:(1)clinical diagnosis or pathological biopsy as HCC; (2) older than 18 years; child-pugh Class A or B; ECOG score aroud 0 to 1; BCLC stage A, B or C; (3) according to the mRECIST (modified response evaluation ciriteriain solid tumor guidelin) standard, at least 1 lesions could be measured; (4) the first therapy towards tumor was TACE; (5) absence of disease of cardiovascular system, lung or renal.According to the inclusion criteria above,132 HCC patient and 50 healthy controlswere enrolled. Venous blood of the HCC patients were collected at 4 time point:before the first TACE treatment(tl), after the first TACE treatment 3-5 days(t2), before the second TACE treatment 4 weeks Iater(t3) and after second TACE treatment 3-5 days(t4). We defined the Change in miRNA-199a/b-3pt1-t2= Serum miR-199a/b-3p levels at t2-serum miR-199a/b-3p levels at t1 Serum miR-199a/b-3p levels at t1TACE was conducted using a mixture of adriamycin, lipiodol, and contrast agent. The dose of adriamycin and lipiodol were dependent on tumor size and vascularity, with 50-100 mg of oxaliplatin,10-20mg of epirubicin,10-20mg mitomycin and lipiodol used per session. Subsequently, embolization was performed using polyvinyl alcohol (PVA) particles or gelatin sponge, and occlusion of target vessels and absence of additional tumor blood supply were confirmed.All patients had follow-up evaluations 4 weeks after first TACE treatment, with routine monitoring by contrast-enhanced computed tomography (CT) or MRI. The modified Response Evaluation Criteria in Solid Tumors (mRECIST) was used to monitor patient response to TACE treatment. Patients with CR and PR were defined as responders(A group), and patients with SD or PD were defined as nonresponders(B group). And collect the clinical datum of cases:age, gender, cirrhosis, tumor size, tumor number, AFP, vascular invasion, Child-Pugh classification and BCLC stage. The study aimed to explore the relationship between serum miR-199a/b-3p expression and clinical datum, the change rule of the serum miR-199a/b-3p expression and the relationship between serum miR-199a/b-3p expression change and TACE treatment response.All data for continuous variables were expressed as mean± standard deviation.The miR-199a/b-3p expression relation between HCC patients and healthy controls was analyzed using Student’s t-test if the data was Gaussian distribution, and if it was not, it was analyzed using two independent sample’s Mann-whitney test. The χ2 test were used to test the association of miR-199a/b-3p with each of the clinicopathological parameters and the relation between miR-199a/b-3p change with TACE treatment response. The results were analyzed using GraphPad Prism software (GraphPad, SanDiego, CA, USA). All statistical tests were two-sided, and P<0.05 was considered significant.Results1. Therapy Results132 HCC patients were treated with TACE as the first treatment towards the tumor, and among them 126 HCC patients was treated with TACE after the first TACE, with 6 HCC patients lossed follow up. Tumor response was evaluated according to mRECIST at 4 weeks after TACE treatment. CR was seen in 15 patients, PR in 35, SD in 62, and PD in 14. Thus,50 patients (CR+PR) were classified as the responder group, and 76 (SD+PD) as the nonresponder group.2. The expression levels of serum miR-199a/b-3p in hepatocellular carcinoma and healthy individualsBaseline expression of serum miR-199a/b-3p in patients (including six patients who missed follow-up) with HCC before TACE (t1) was significantly lower than that of the healthy controls subjects (0.68±0.81 vs 2.50±2.16, P<0.001). The median expression level of serum miR-199a/b-3p in HCC patients was 0.267.3. Correlation between serum miR-199a/b-3p expression levels and clinicopathologic characteristics of patients with HCCTo understand whether there is a correlation between serum miR-199a/b-3p expression levels and clinicopathologic characteristics of patients with HCC, we divided the 132 patients into two groups:a lower expression group and a higher expression group. We found that lower levels of serum miR-199a/b-3p correlated with larger tumor size (P<0.001). Expression levels of serum miR-199a/b-3p were not significantly different with hepatitis B surface antigen (HBsAg) status, presence of vascular invasion or cirrhosis, BCLC stage, Child-Pugh classification, or level of AFP.4. Correlation between serum miR-199a/b-3p expression levels at different timepoints and TACE treatment responseThe results demonstrated that the nonresponder group had significantly lower miR-199a/b-3p expression than the responder group at t1 (0.77±1.09 vs 1.96±1.32, P0.001).5. Correlation between serum miR-199a/b-3p expression level changes and TACE treatment responseThe decrease in miR-199a/b-3pt1-t was greater in responder group than in the nonresponder group (P=0.011). A higher proportion of the responder group achieved a>25% decrease in serum miR-199a/b-3p levels compared with the nonresponder group (64% vs 39%).ConclusionsSerum miR-199a/b-3p had the potential to be a biomarker to early predict the TACE treatment response. Baseline expression of serum miR-199a/b-3p in HCC patients was significantly lower than that of the healthy controls subjects, and the expression level was negative relation with tumor size. The pre-TACE serum miR-199a/b-3p level was positive relation with the treatment response, and the decrease in miR-199a/b-3p between the first TACE was significantly correlated with TACE treatment response. |
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