Hepatitis B virus X protein-mediated upregulation of miR-221 activates the CXCL12-CXCR4 axis to promote NKT cells in HBV-related hepatocellular carcinoma

作者全名："Cao, Y. U. E.; Hu, L. I. N.; Tang, Y. I. S. H. U."

作者地址："[Cao, Y. U. E.; Hu, L. I. N.; Tang, Y. I. S. H. U.] Chongqing Med Univ, Dept Lab Med, Affiliated Hosp 1, Chongqing 400016, Peoples R China"

通信作者："Tang, YS (通讯作者)，Chongqing Med Univ, Dept Lab Med, Affiliated Hosp 1, Chongqing 400016, Peoples R China."

来源：BIOCELL

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001026329100010

JCR分区：Q4

影响因子：0.8

年份：2023

卷号：47

期号：7

开始页：1537

结束页：1548

文献类型：Article

关键词：& nbsp; Hepatitis B virus X protein; miR-221; Hepatocellular carcinoma; CXCL12; NKT

摘要："Backgrounds: Both hepatitis B virus X protein (HBx) and microRNA-221 (miR-221) have been implicated in the development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). The present study demonstrates that HBx promotes HCC cell proliferation via the C-X-C motif chemokine ligand 12-C-X-C chemokine receptor type 4 (CXCL12-CXCR4) axis. We predict that HBx/miR-221-mediated CXCL12/CXCR4 signaling induces NKT cells to promote HBV-related HCC. Methods: After miR-221 mimic, miR-221 mimic negative control, miR-221 inhibitor, miR-221 inhibitor negative control were transfected into cells, the expression of CXCL12 and miR-221 was detected by qPCR and western blot. Then we constructed a stable HBV-HCC cell line. HBV-HCC cells were injected into the nude mice, thus a HBV-HCC mouse model was constructed. Q-PCR and western blot were used to detect the expression of HBx, miR-221, CXCL12 and CXCR4 in tumor tissues. The expression of CXCL12 was detected by immunohistochemistry, and the expression of CXCR4, CD3 and CD56 was detected by immunofluorescence. The levels of CXCL12, IL-2 and TNF-& alpha; in serum of mice were detected by ELISA. Sixty-one patients with HBV-related HCC, 61 patients with HBV-related cirrhosis, 61 patients with chronic hepatitis B (CHB) and 30 healthy people were enrolled. CXCL12, cytokine levels, and clinicopathological parameters were tested. Results: Hepatitis B virus X protein upregulates the expression of miR-221 and CXCL12 in lentivirus (LV5)-HBx-transfected HepG2 cells. HBx protein promotes HepG2 cell proliferation in vitro. HBx protein promoted tumor growth via the miR-221/CXCL12/ CXCR4 pathway in a mouse tumor model. HBx protein upregulated natural killer T cell expression via the CXCR4/ CXCL12 pathway to promote tumor growth. The data demonstrated a positive correlation between CXCL12 concentration with Cre levels and Child-Pugh scores. CXCL12 had an inferior diagnostic efficiency compared to IL-2 and IL-6 for HBV-related HCC. Conclusions: We present evidence that HBx/miR-221-mediated CXCL12/CXCR4 signaling induces NKT cells to promote HBV-related HCC."

基金机构："National Natural Science Foundation of Chongqing, China [cstc2019jcyj-msxm0314]; National Key Ramp;D Program of China [2017YFC0909902]; Natural Science Foundation of China [81501818]"

基金资助正文："Funding Statement: This study was supported by the National Natural Science Foundation of Chongqing, China (No. cstc2019jcyj-msxm0314 of Yishu Tang) , the National Key R & D Program of China (No. 2017YFC0909902 of Yun Xia) , and the Natural Science Foundation of China (No. 81501818 of Yishu Tang) ."