Renal Dysfunction In Elderly Chronic Hepatitis B Patients With Adefovir Dipivoxil Treatment And The Effect Of WAVE3 Overexpress On Hepatocellular Carcinoma Prognosis

Objective:To assess the benefits of long-term low-dose adefovir dipivoxil (ADV) therapy for elderly patients with chronic hepatitis B (CHB) and to investiage the relationship between age and the emergence rate of renal dysfunction comprehensively. To detect the expression of WAVE3 in HCC tissues and evaluate its impact on prognostic, further, study the effect of WAVE3 on tumor cells of HCCs.Methods:The cohort included 242 CHB patients treated with 10 mg/day ADV for more than six months, which were divided into the young (90), middle-aged (106), and old (46) groups based on their ages. The estimated glomerular filtration rate (eGFR) was calculated to present renal function. Serum creatinine and hepatitis B virus (HBV) DNA were detected.In the second study, a total of 120 paired of formalin-fixed and paraffin-embedded cancerous and adjacent noncancerous tissues from patients with HCC were used to detect the expression pattern of WAVE3 by using immunohistochemistric analysis. Then, the associations of WAVE3 expression with clinicopathologic characteristics of HCC and patients’ prognosis were examined. The roles of WAVE3 in migration and invasion of HCC cell line HepG2 were also evaluated in vitro.Results:The cumulative incidence (CI) of renal impairment (defined as eGFR<50 ml/min/1.73m2 or eGFR was reduced by≥30% relative to baseline) was significantly higher in the elderly patients (19.57%) in comparison with the middle-aged (7.55%) and yong (3.33%) patients at 144 weeks of ADV treatment (P<0.01).17 of 20 patients developing ADV-induced renal impairment had no drug-resistant mutations, and the eGFR was increased by continuous treatment with entecavir (ETV). The rental function of 3 patients showing lamivudine resistance was improved by adjusting ADV doses. In addition, ADV treatment reduced HBV DNA but increased serum creatinine.Positive immunostaining of WAVE3 was predominantly observed in the cytoplasm of HCC cells. Compared to adjacent non-cancerous tissues, the expression levels of WAVE3 protein was significantly upregulated in HCC tissues (P<0.001). In addition, high WAVE3 expression was significantly associated with two clinicopathologic features of HCC including advanced tumor stage (P=0.008) and positive distant metastasis (P=0.001). Then, high WAVE3 expression correlated significantly with poor prognosis, and WAVE3 status was identified as an independent significant prognostic factor. Moreover, small interfering RNA targeting WAVE3 was used to inhibit the expression of WAVE3 in HepG2 cells. We found that suppression of WAVE3 could inhibit migration and invasion of HepG2 cells.Conclusion:The first study suggest that the CI of renal dysfunction caused by long-term low-dose (10 mg/day) ADV therapy was positively associated with age, and renal impairment occurred more frequently in ealerly CHB patients. The ADV-induced renal impairment could be improved either by replacing ADV with ETV or by adjusting ADV doses. This study provides new insights into clinical application of ADV in elderly CHB patients. The second study have characterized WAVE3 as biomarker for HCC progression and metastasis, and more importantly, have identified it as an independent prognostic marker for HCC patients. Our data also indicated that WAVE3 is pivotal in controlling oncogenic phenotypes of human HCC cells.