Screening of hepatoma-derived growth factor with highly expression in HCC bone metastasis and its cellular biological effects

Xi ZHANG; Yongpeng HE; Gaohai SHAO

doi:10.16016/j.2097-0927.202404047

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Screening of hepatoma-derived growth factor with highly expression in HCC bone metastasis and its cellular biological effects

Basic Medicine | 更新时间：2026-01-09

- Screening of hepatoma-derived growth factor with highly expression in HCC bone metastasis and its cellular biological effects
- Journal of Army Medical University Vol. 46, Issue 23, Pages: 2620-2628(2024)
- 作者机构：
  
  1.402177 重庆，重庆医科大学附属永川医院骨科
  2.400000 重庆，重庆大学附属肿瘤医院肝胆胰肿瘤中心
- 作者简介：
- 基金信息：
  
  the Special Key Project of Technological Innovation and Application Development of Chongqing(CSTB2022TIAD-KPX0172);the Special General Project of Technological Innovation and Application Development of Chongqing(2022yc-cxfz30008);the General Project of Natural Science Foundation of Chongqing(CSTB2023NSCQ-MSX0821);the Project of Chongqing Medicinal Biotech Association(cmba2022kyym-zkxmQ0012);the Joint Medical Research Project of Shapingba Science and Technology Commission and Health Commission(2023SQKWLH23)
- DOI：10.16016/j.2097-0927.202404047
  CLC： R730.23;R735.7;R738.1
- Received：13 April 2024，
  
  Revised：2024-08-10，
  
  Published：15 December 2024
- 稿件说明：
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Xi ZHANG, Yongpeng HE, Gaohai SHAO. Screening of hepatoma-derived growth factor with highly expression in HCC bone metastasis and its cellular biological effects[J]. Journal of Army Medical University, 2024, 46(23): 2620-2628.
DOI：

Xi ZHANG, Yongpeng HE, Gaohai SHAO. Screening of hepatoma-derived growth factor with highly expression in HCC bone metastasis and its cellular biological effects[J]. Journal of Army Medical University, 2024, 46(23): 2620-2628. DOI： 10.16016/j.2097-0927.202404047.

摘要

目的

探究肝癌衍生生长因子(hepatoma-derived growth factor

HDGF)在肝细胞癌(hepatocellular carcinoma

HCC)中的表达，以及其对DNA损伤、增殖、迁移、上皮-间质转化(epithelial mesenchymal transition

EMT)以及骨保护素(osteoprotegerin

OPG)的表达影响作用。

方法

分析GEO数据库中HCC骨转移患者与HCC非转移患者的肝脏肿瘤中mRNA的差异表达特征，筛选出差异最显著基因HDGF。利用qRT-PCR技术验证HDGF mRNA在转移能力不同的HCC细胞中的表达情况。分别通过γ-H2AX免疫荧光实验，分析不同组肝癌细胞的DNA损伤程度。采取Cell counting Kit-8试剂盒、集落形成实验和Transwell迁移实验检测HDGF对细胞增殖、迁移能力的影响。通过蛋白质印迹法，检测EMT相关蛋白Vimentin、E-cadherin在不同程度骨转移组HCC细胞中的表达差异。运用qRT-PCR技术和蛋白质印记法(western blot，WB)检测各组肝癌细胞中OPG的差异表达。

结果

HDGF在骨转移的HCC组织和高转移性HCC细胞系中高表达；HDGF高表达能够抑制细胞DNA损伤修复；HDGF能够促进HCC细胞系增殖、迁移；HDGF上调Vimentin的蛋白表达水平，同时下调E-cadherin的蛋白表达水平(

均＜0.05)，且HDGF过表达下调了OPG的表达。

结论

HDGF在骨转移肝细胞瘤中高表达，并可能通过促进EMT、迁移和增殖而促进骨转移。

Abstract

Objective

To investigate the expression of hepatoma-derived growth factor (HDGF) in hepatocellular carcinoma (HCC) and its effects on DNA damage

proliferation

migration

epithelial mesenchymal transition (EMT)

and expression of osteoprotegerin (OPG) in HCC cells.

Methods

GEO database was analyzed to obtain the expression features of differential expressed mRNAs in liver tumors between HCC patients with bone metastasis and those without

and then HDGF was found as the most significantly differentially expressed gene. The mRNA expression of HDGF was verified in the HCC cells with varying metastatic capabilities by qRT-PCR. DNA damage levels in different groups of liver cancer cells were analyzed through γ-H2AX immunofluorescence assay. The effects of HDGF on cell proliferation and migration were detected with CCK-8 assay

colony formation assay

and Transwell migration assay. Western blotting was employed to measure the expression of EMT-related proteins Vimentin and E-cadherin in HCC cells with various capacities of bone metastasis. Then qRT-PCR and Western blotting were performed to determine the differential expression of OPG in various groups of liver cancer cells.

Results

HDGF was highly expressed in HCC tissues with bone metastasis and in high-metastatic HCC cell lines. High expression of HDGF inhibited DNA damage repair. HDGF promoted the proliferation and migration of HCC cell lines. HDGF up-regulated the protein expression level of Vimentin while down-regulated that of E-cadherin (both

0.05)

and overexpression of HDGF down-regulated the expression of OPG.

Conclusion

HDGF is highly expressed in bone metastatic hepatocellular tumors and may promote bone metastasis by facilitating EMT

migration

and proliferation.

关键词

Keywords

references

BRAY F, LAVERSANNE M, SUNG H, et al . Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J ] . CA Cancer J Clin, 2024, 74(3): 229-263. DOI: 10.3322/caac.21834.

HUANG Z, WEN J Y, WANG Y F, et al . Bone metastasis of hepatocellular carcinoma: facts and hopes from clinical and translational perspectives[J ] . Front Med, 2022, 16(4): 551-573. DOI: 10.1007/s11684-022-0928-z.

OZER M, GOKSU S Y, LIN R Y, et al . Effects of clinical and tumor characteristics on survival in patients with hepatocellular carcinoma with bone metastasis[J ] . J Hepatocell Carcinoma, 2023, 10: 1129-1141. DOI: 10 .2147/JHC.S417273.

WEILBAECHER K N, GUISE T A, MCCAULEY L K. Cancer to bone: a fatal attraction[J]. Nat Rev Cancer, 2011, 11(6): 411-425. DOI: 10.1038/nrc3055.

HEMINGWAY F, TAYLOR R, KNOWLES H J, et al . RANKL-independent human osteoclast formation with APRIL, BAFF, NGF, IGF Ⅰ and IGF Ⅱ[J ] . Bone, 2011, 48(4): 938-944. DOI: 10.1016/j.bone.2010.12.023.

CHEN S X, LEI J C, MOU H C, et al . Multiple influence of immune cells in the bone metastatic cancer microenvironment on tumors[J ] . Front Immunol, 2024, 15: 1335366. DOI: 10.3389/fimmu.2024.1335366.

HANAHAN D. Hallmarks of cancer: new dimensions[J]. Cancer Discov, 2022, 12(1): 31-46. DOI: 10.1158/2159-8290.CD-21-1059.

HONG W F, ZHANG Y, WANG S W, et al . Deciphering the immune modulation through deep transcriptomic profiling and therapeutic implications of DNA damage repair pattern in hepatocellular carcinoma[J ] . Cancer Lett, 2024, 582: 216594. DOI: 10.1016/j.canlet.2023.216594.

KLAGSBRUN M, SASSE J, SULLIVAN R, et al . Human tumor cells synthesize an endothelial cell growth factor that is structurally related to basic fibroblast growth factor[J ] . Proc Natl Acad Sci U S A, 1986, 83(8): 2448-2452. DOI: 10.1073/pnas.83.8.2448.

ENOMOTO H, NAKAMURA H, LIU W, et al . Hepatoma-derived growth factor: its possible involvement in the progression of hepatocellular carcinoma[J ] . Int J Mol Sci, 2015, 16(6): 14086-14097. DOI: 10.3390/ijms160614086.

LI Y T, DITTMANN N L, EVE A, et al . Hepatoma derived growth factor enhances oligodendrocyte genesis from subventricular zone precursor cells[J ] . ASN Neuro, 2022, 14: 17590914221086340. DOI: 10.1177/17590914221086340.

WANG E M, HU T H, HUANG C C, et al . Hepatoma-derived growth factor participates in concanavalin A-induced hepatitis[J ] . FASEB J, 2020, 34(12): 16163-16178. DOI: 10.1096/fj.202000511RR.

YANG J, AMBADE A S, NIES M, et al . Hepatoma-derived growth factor is associated with pulmonary vascular remodeling and PAH disease severity and survival[J ] . Pulm Circ, 2022, 12(1): e12007. DOI: 10.1002/pul2.12007.

HUGE N, REINKENS T, BUURMAN R, et al . MiR-129-5p exerts Wnt signaling-dependent tumor-suppressive functions in hepatocellular carcinoma by directly targeting hepatoma-derived growth factor HDGF[J ] . Cancer Cell Int, 2022, 22(1): 192. DOI: 10.1186/s12935-022-02582-2.

ELTAHIR H M. Insight into the roles of hepatoma derived growth factor related protein-3 under physiological and pathological conditions[J]. Biochem Cell Biol, 2018, 96(6): 707-712. DOI: 10.1139/bcb-2018-0098.

CHANG K C, TAI M H, LIN J W, et al . Hepatoma-derived growth factor is a novel prognostic factor for gastrointestinal stromal tumors[J ] . Int J Cancer, 2007, 121(5): 1059-1065. DOI: 10.1002/ijc.22803.

CHU T H, HUANG S T, YANG S F, et al . Hepatoma-derived growth factor participates in Helicobacter pylori -induced neutrophils recruitment, gastritis and gastric carcinogenesis[J ] . Oncogene, 2019, 38(37): 6461-6477. DOI: 10.1038/s41388-019-0886-3..

KOH H M, HYUN C L, JANG B G, et al . The relationship between hepatoma-derived growth factor and prognosis in non-small cell lung cancer: a systematic review and meta-analysis[J ] . Medicine, 2020, 99(51): e23837. DOI: 10.1097/MD.000000 0000023837.

WUPUTRA K, KU C C, PAN J B, et al . Independent signaling of hepatoma derived growth factor and tumor necrosis factor-alpha in human gastric cancer organoids infected by Helicobacter pylori [J ] . Int J Mol Sci, 2023, 24(7): 6567. DOI: 10.3390/ijms24076567..

CHEN X Y, YUN J, FEI F, et al . Prognostic value of nuclear hepatoma-derived growth factor (HDGF) localization in patients with breast cancer[J ] . Pathol Res Pract, 2012, 208(8): 437-443. DOI: 10.1016/j.prp.2012.03.004.

HAN S Y, TIAN Z H, TIAN H F, et al . HDGF promotes gefitinib resistance by activating the PI3K/AKT and MEK/ERK signaling pathways in non-small cell lung cancer[J ] . Cell Death Discov, 2023, 9(1): 181. DOI: 10.1038/s41420-023-01476-0.

LEPOURCELET M, TOU L Q, CAI L, et al . Insights into developmental mechanisms and cancers in the mammalian intestine derived from serial analysis of gene expression and study of the hepatoma-derived growth factor (HDGF)[J ] . Development, 2005, 132(2): 415-427. DOI: 10.1242/dev.01579.

UCHINO K, TATEISHI R, SHIINA S, et al . Hepatocellular carcinoma with extrahepatic metastasis: clinical features and prognostic factors[J ] . Cancer, 2011, 117(19): 4475-4483. DOI: 10.1002/cncr.25960.

UKA K, AIKATA H, TAKAKI S, et al . Clinical features and prognosis of patients with extrahepatic metastases from hepatocellular carcinoma[J ] . World J Gastroenterol, 2007, 13(3): 414-420. DOI: 10.3748/wjg.v13.i3.414.

CHUNG C L, WU C H, HUANG Y H, et al . Blocking hepatoma-derived growth factor attenuates vasospasm and neuron cell apoptosis in rats subjected to subarachnoid hemorrhage[J ] . Transl Stroke Res, 2022, 13(2): 300-310. DOI: 10.1007/s12975-021-00928-y.

WANG C, JIANG K, KANG X N, et al . Tumor-derived secretory clusterin induces epithelial-mesenchymal transition and facilitates hepatocellular carcinoma metastasis[J ] . Int J Biochem Cell Biol, 2012, 44(12): 2308-2320. DOI: 10.1016/j.biocel.2012.09.012.

LIU X J, LIU W L, YANG F M, et al . Hepatoma-derived growth factor predicts unfavorable prognosis of epithelial ovarian cancer[J ] . Onco Targets Ther, 2015, 8: 2101-2109. DOI: 10.2147/OTT.S85660.

BUIJS J T, VAN DER PLUIJM G. Osteotropic cancers: from primary tumor to bone[J]. Cancer Lett, 2009, 273(2): 177-193. DOI: 10.1016/j.canlet.2008.05.044.

MICALIZZI D S, FARABAUGH S M, FORD H L. Epithelial-mesenchymal transition in cancer: parallels between normal development and tumor progression[J]. J Mammary Gland Biol Neoplasia, 2010, 15(2): 117-134. DOI: 10.1007/s10911-010-9178-9.

LU Z, NI H H, YANG X H, et al . Prognostic potential of preoperative circulating tumor cells to predict the early progression recurrence in hepatocellular carcinoma patients after hepatectomy[J ] . BMC Cancer, 2023, 23(1): 1150. DOI: 10.1186/s12885-023-11629-0.

REICHL P, HAIDER C, GRUBINGER M, et al . TGF-β in epithelial to mesenchymal transition and metastasis of liver carcinoma[J ] . Curr Pharm Des, 2012, 18(27): 4135-4147. DOI: 10.2174/138161212802430477.

LORD C J, ASHWORTH A. The DNA damage response and cancer therapy[J]. Nature, 2012, 481(7381): 287-294. DOI: 10.1038/nature10760.

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