Open Access

Low‑intensity ultrasound enhances the antitumor effects of doxorubicin on hepatocellular carcinoma cells through the ROS‑miR‑21‑PTEN axis

  • Authors:
    • Chunhua Xia
    • Huabei Zeng
    • Yanfen Zheng
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  • Published online on: January 13, 2020     https://doi.org/10.3892/mmr.2020.10936
  • Pages: 989-998
  • Copyright: © Xia 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 a type of liver cancer and is a leading cause of cancer‑associated mortality. In China, ~466,000 patients are diagnosed with HCC and it is responsible for ~422,000 cases of mortality each year. Surgery is the most effective treatment available; however it is only suitable for patients with early‑stage HCC. Chemotherapy has been confirmed as a necessary treatment for patients with advanced HCC, although drug resistance may limit its clinical outcome. Low intensity ultrasound (LIUS) represents a novel therapeutic approach to treat patients with HCC; however, its underlying molecular mechanism remains unclear. In the present study, cell viability, apoptosis and reactive oxygen species (ROS) generation were determined via Cell Counting Kit‑8, flow cytometry and 2',7'‑dichlorofluorescein diacetate assays, respectively. The expression of miRNA in HCC cells following exposure to LIUS and doxorubicin (Dox) was analyzed using a microarray and reverse transcription‑quantitative polymerase chain reaction analysis. It was revealed treatment with LIUS in combination with Dox was able to induce apoptosis of Huh7 cells, increasing the intracellular levels of reactive oxygen species (ROS) and malondialdehyde. Glutathione peroxidase and superoxide dismutase 1 are ROS‑scavenging enzymes, which serve important roles in the oxidative balance, preventing oxidative stress. The protein expression levels of these two enzymes were significantly decreased following treatment with LIUS combined with Dox. The present results suggested that LIUS may decrease Dox resistance in HCC cells and that LIUS may be combined with chemotherapy to treat HCC. By performing microarray analysis, the expression levels of microRNA‑21 (miR‑21) were decreased following treatment with LIUS combined with Dox. Functional experiments showed that knockdown of miR‑21 enhanced the antitumor activity of Dox, whereas overexpression of miR‑21 reversed these effects. Phosphatase and tensin homolog (PTEN), a well‑known tumor suppressor, was revealed to be a direct target of miR‑21, and its translation was suppressed by miR‑21. Finally, it was determined that combined treatment of LIUS and Dox induced anticancer effects by blocking the activation of the AKT/mTOR pathway, as demonstrated by the downregulation of phosphorylated (p‑)AKT and p‑mTOR; N‑acetylcysteine, a general ROS inhibitor reversed the suppressive effects on the AKT/mTOR pathway mediated by LIUS and Dox. Collectively, the present results suggested that LIUS increased cell sensitivity to Dox via the ROS/miR‑21/PTEN pathway. Chemotherapy combined with LIUS may represent a novel effective therapeutic strategy to treat patients with advanced HCC.
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March 2020
Volume 21 Issue 3

Print ISSN: 1791-2997
Online ISSN:1791-3004

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APA
Xia, C., Zeng, H., & Zheng, Y. (2020). Low‑intensity ultrasound enhances the antitumor effects of doxorubicin on hepatocellular carcinoma cells through the ROS‑miR‑21‑PTEN axis. Molecular Medicine Reports, 21, 989-998. https://doi.org/10.3892/mmr.2020.10936
MLA
Xia, C., Zeng, H., Zheng, Y."Low‑intensity ultrasound enhances the antitumor effects of doxorubicin on hepatocellular carcinoma cells through the ROS‑miR‑21‑PTEN axis". Molecular Medicine Reports 21.3 (2020): 989-998.
Chicago
Xia, C., Zeng, H., Zheng, Y."Low‑intensity ultrasound enhances the antitumor effects of doxorubicin on hepatocellular carcinoma cells through the ROS‑miR‑21‑PTEN axis". Molecular Medicine Reports 21, no. 3 (2020): 989-998. https://doi.org/10.3892/mmr.2020.10936