Research Paper Volume 15, Issue 22 pp 13010—13040

Identification of topoisomerase 2A as a novel bone metastasis-related gene in liver hepatocellular carcinoma

Jinyan Feng1,2,3, *, , Xianfu Wei1,2,3, *, , Yongheng Liu1,2,3, , Yanting Zhang1,2,3, , Guanghao Li1,2,3, , Yao Xu1,2,3, , Peng Zhou1,2,3,4, , Jin Zhang1,2,3, , Xiuxin Han1,2,3, , Chao Zhang1,2,3, , Yan Zhang1,2,3, , Guowen Wang1,2,3, ,

  • 1 Department of Bone and Soft Tissue Tumors, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China
  • 2 Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
  • 3 Tianjin’s Clinical Research Center for Cancer, Tianjin, China
  • 4 Department of Orthopedics, Affiliated Hospital of Chifeng University, Chifeng, China
* Equal contribution

Received: February 13, 2023       Accepted: October 17, 2023       Published: November 17, 2023
How to Cite

Copyright: © 2023 Feng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Background: Bone is the second most frequent site of metastasis for Liver hepatocellular carcinoma (LIHC), which leads to an extremely poor prognosis. Identifying novel biomarkers and therapeutic targets for LIHC patients with bone metastasis is urgently needed.

Methods: In this study, we used multiple databases for comprehensive bioinformatics analysis, including TCGA, GEO, ICGC, GTEx, TISIDB, and TIMER, to identify key genes related to bone metastasis of LIHC. Clinical tissues and tissue microarray were adopted to assess the expression of TOP2A through qRT-PCR and immunohistochemistry analyses in LIHC. Gene enrichment analysis, DNA methylation, gene mutation, prognosis, and tumor immunity associated with TOP2A in LIHC were investigated. In vitro and in vivo experiments were performed to explore the functional role of TOP2A in LIHC bone metastasis.

Results: We identified that TOP2A was involved in LIHC bone metastasis. Clinically, TOP2A was highly expressed in LIHC tumoral specimens, with the highest level in the bone metastasis lesions. TOP2A was an independent prognostic factor that higher expression of TOP2A was markedly associated with poorer prognosis in LIHC. Moreover, the abnormal expression of TOP2A might be related to DNA hypomethylation, often accompanied by TP53 mutation, immune escape and immunotherapy failure. Enrichment analysis and validation experiments unveiled that TOP2A stimulated the Hippo-YAP signaling pathway in LIHC. Functional assays confirmed that TOP2A could promote bone-specific metastatic potential and tumor-induced osteolysis in LIHC.

Conclusions: These findings unveil that TOP2A might be a novel prognostic biomarker and therapeutic target for LIHC bone metastasis.


ACC: adrenocortical carcinoma; BLCA: bladder urothelial carcinoma; BRCA: breast invasive carcinoma; CESC: cervical and endocervical cancer; CHOL: cholangiocarcinoma; COAD: colon adenocarcinoma; DLBC: diffuse large B-cell lymphoma; ESCA: esophageal carcinoma; GBM: glioblastoma multiforme; HNSC: head and neck cancer; HNSC-HPV +: head and neck cancer-HPV positive; HNSC-HPV −: head and neck cancer-HPV negative; KICH: kidney chromophobe; KIRC: kidney renal clear cell carcinoma; KIRP: kidney renal papillary cell carcinoma; LAML: acute myeloid leukemia; LGG: lower grade glioma; LIHC: liver hepatocellular carcinoma; LUAD: lung adenocarcinoma; LUSC: lung squamous cell carcinoma; MESO: mesothelioma; OV: ovarian serous cystadenocarcinoma; PAAD: pancreatic adenocarcinoma; PCPG: pheochromocytoma and paraganglioma; PRAD: prostate adenocarcinoma; READ: rectum adenocarcinoma; SARC: sarcoma; SKCM: skin cutaneous melanoma; STAD: stomach adenocarcinoma; TGCT: testicular germ cell tumors; THCA: thyroid carcinoma; THYM: thymoma; UCEC: uterine corpus endometrial carcinoma; UCS: uterine carcinosarcoma; UVM: uveal melanoma.