STAT3 regulates the migration and invasion of a stem‑like subpopulation through microRNA‑21 and multiple targets in hepatocellular carcinoma.

Abstract

Despite advances in the detection and treatment of hepatocellular carcinoma (HCC), the prognosis remains poor partly due to recurrence or extra/intrahepatic metastasis. Stem‑like cancer cells are considered the source of malignant phenotypes including metastasis in various types of cancer. HCC side population (SP), considered as stem‑like cancer cells, plays an important role in the migration and invasion in HCC, while the mechanisms involved remain unknown. In the present study, high levels of STAT3 and phospho‑STAT3 were observed in MHCC97H SP cells compared with the main population (MP) cells. Inhibition of phospho‑STAT3 led to a reduction of miR‑21 expression, an increase of PTEN, RECK, and programmed cell death 4 (PDCD4) expression as well as the migration and invasion of SP cells. A set of rescue experiments was performed using different combinations of STAT3 inhibitor, miR‑21 mimics and siRNAs to observe the expression of miR‑21 targets, cell migration and invasion alterations. Data indicated that the alterations induced by STAT3 inhibition were partly reversed by the upregulation of miR‑21. Additionally, the cells migration and invasion when silencing the targets of miR‑21 were also reversed by STAT3 inhibition. In conclusion, the present study revealed the aberrant expression of STAT3 and miR‑21 in HCC SP cells. Targeting STAT3 may limit HCC migration and invasion, which is likely to involve the regulation of miR‑21 and its targets PTEN, RECK and PDCD4. Strategies directed towards STAT3 may therefore be a novel approach for the treatment of HCC.