Comprehensive analysis of circulating microRNAs as predictive biomarkers for sorafenib therapy outcome in hepatocellular carcinoma

Kohno,Tomoki; Morishita,Asahiro; Iwama,Hisakazu; Fujita,Koji; Tani,Joji; Takuma,Kei; Nakahara,Mai; Oura,Kyoko; Tadokoro,Tomoko; Nomura,Takako; Yoneyama,Hirohito; Kato,Kiyohito; Okano,Keiichi; Suzuki,Yasuyuki; Nishiyama,Akira; Himoto,Takashi; Masaki,Tsutomu

doi:10.3892/ol.2020.11696

Comprehensive analysis of circulating microRNAs as predictive biomarkers for sorafenib therapy outcome in hepatocellular carcinoma

Authors:
- Tomoki Kohno
- Asahiro Morishita
- Hisakazu Iwama
- Koji Fujita
- Joji Tani
- Kei Takuma
- Mai Nakahara
- Kyoko Oura
- Tomoko Tadokoro
- Takako Nomura
- Hirohito Yoneyama
- Kiyohito Kato
- Keiichi Okano
- Yasuyuki Suzuki
- Akira Nishiyama
- Takashi Himoto
- Tsutomu Masaki
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Affiliations: Department of Gastroenterology and Neurology, Kagawa University Faculty of Medicine, Kita‑gun, Kagawa 761‑0793, Japan, Life Science Research Center, Kagawa University Faculty of Medicine, Kita‑gun, Kagawa 761‑0793, Japan, Department of Gastroenterological Surgery, Kagawa University Faculty of Medicine, Kita‑gun, Kagawa 761‑0793, Japan, Department of Pharmacology, Kagawa University Faculty of Medicine, Kita‑gun, Kagawa 761‑0793, Japan, Department of Medical Technology, Kagawa Prefectural University of Health Sciences, Takamatsu, Kagawa 761‑0123, Japan
Published online on: June 5, 2020 https://doi.org/10.3892/ol.2020.11696
Pages: 1727-1733
Copyright: © Kohno et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer‑related death worldwide. Clinical management has improved the prognosis of early HCC, but that of advanced HCC remains poor. Sorafenib, an oral multikinase inhibitor, provided a treatment option for advanced‑stage HCC, and prolonged the survival and inhibited tumor progression as first‑line therapy in patients with advanced HCC. In this study, we investigated if specific microRNAs could act as predictive biomarkers of sorafenib effectiveness and indicate the best time to switch to second‑line therapies. Sorafenib inhibited the proliferation of the Li‑7, Hep3B, HepG2 and Huh7 liver cancer cell lines (effective group), but not that of the HLE, HLF and ALEX cancer cell lines (non‑effective group). A microRNA (miRNA/miR) analysis was performed comparing sorafenib‑effective and non‑effective cells lines as well as serum samples from patients with HCC from sorafenib‑effective (complete response/partial response) and ‑non‑effective (progressive disease) groups before sorafenib administration and detected three differentially‑expressed miRNAs that were common among the in vivo and in vitro samples. The increase rate (effective/non‑effective) of hsa‑miR‑30d in the medium was higher than that in the cancer cells. hsa‑miR‑30d was highly expressed in the serum and exosomes of patients with HCC in the effective group when compared to those of the non‑effective group. Additionally, the hsa‑miR‑30d expression in the medium of cancer cell lines was highly upregulated in the effective group compared with the non‑effective group. These results suggested that hsa‑miR‑30d might be secreted by the cancer cells to the serum through the exosomes. We identified a specific circulating miRNA that is related to refractory HCC under sorafenib therapy. Therefore, hsa‑miR‑30d might serve as a predictive biomarker for the efficacy of sorafenib therapy in HCC.

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