J Cancer 2020; 11(17):5118-5128. doi:10.7150/jca.45995

Research Paper

LncZEB1-AS1 regulates hepatocellular carcinoma bone metastasis via regulation of the miR-302b-EGFR-PI3K-AKT axis

Zhen-jiang Ma1,2*, Yao Wang3,4*, Hui-fen Li5*, Ming-Hua Liu3, Feng-rui Bi3, Long Ma3, Hui Ma1✉, Hong-li Yan3✉

1. Department of Orthopedics, the Third Affiliated Hospital of Second Military Medical University, Shanghai 201805, P.R. China.
2. Department of Orthopedics, Shanghai Ninth People's Hospital, Shanghai 200011, P.R. China.
3. Department of Laboratory Medicine, Changhai Hospital, Second Military Medical University, Shanghai, P.R. China.
4. Department of Laboratory Medicine, The Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi, Jiangsu 214000, China.
5. Department of Interventional, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, P.R. China.
*These authors contributed equally to this work.

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Citation:
Ma Zj, Wang Y, Li Hf, Liu MH, Bi Fr, Ma L, Ma H, Yan Hl. LncZEB1-AS1 regulates hepatocellular carcinoma bone metastasis via regulation of the miR-302b-EGFR-PI3K-AKT axis. J Cancer 2020; 11(17):5118-5128. doi:10.7150/jca.45995. Available from http://www.jcancer.org/v11p5118.htm

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Abstract

In patients with hepatocellular carcinoma (HCC), disease progression and associated bone metastasis (BM) can markedly reduce quality of life. While the long non-coding RNA (lncRNA) zinc finger E-box binding homeobox 1 antisense 1 (ZEB1-AS1) has been shown to function as a key regulator of oncogenic processes in HCC and other tumor types, whether it plays a role in controlling HCC BM remains to be established. In the current study, we detected the significant upregulation of lncZEB1-AS1 in HCC tissues, and we found this expression to be associated with BM progression. When we knocked down this lncRNA in HCC cells, we found that this significantly reduced their migratory, invasive, and metastatic activity both in vitro and in vivo. At a mechanistic level, we found that lncZEB1-AS1 was able to target miR-302b and to thereby increase PI3K-AKT pathway activation and EGFR expression, resulting in the enhanced expression of downstream matrix metalloproteinase genes in HCC cells. In summary, our results provide novel evidence that lncZEB1-AS1 can promote HCC BM through a mechanism dependent upon the activation of PI3K-AKT signaling, thus highlighting a potentially novel therapeutic avenue for the treatment of such metastatic progression in HCC patients.

Keywords: Hepatocellular carcinoma, Bone metastasis, LncZEB1-AS1, miR-302b, EGFR-PI3K-AKT axis