Tumor Biology

, Volume 36, Issue 5, pp 3643–3651 | Cite as

MAPK inhibitors differently modulate TGF-β/Smad signaling in HepG2 cells

Research Article


The aim of this study was to investigate the mitogen-activated protein kinase (MAPK) pathway, which crosstalk with TGF-β/Smad signaling via linker phosphorylation of Smad2/3 to promote hepatocarcinogenesis. After DEN-induced hepatocellular carcinoma (HCC) in rats showed increased phosphorylation of JNK1/2, p38, and ERK1/2, we next antagonized TGF-β1-induced phosphorylation of JNK1/2, p38, ERK1/2, Smad2/3 signaling in HepG2 cells using SP600125, SB203580, and PD98059, respectively. Cell proliferation and invasion were assessed by MTT assay and transwell invasion chambers, respectively. Smad2/3, Smad4, and Smad7 expressions and PAI-1 messenger RNA (mRNA) transcription were measured by using immuno-precipitation/immuno-blotting and real-time RT-PCR, respectively. All the MAPK-specific inhibitors suppressed cell invasion, while all but PD98059 suppressed cell proliferation. Both SP600125 and SB203580 blocked pSmad2C/L and oncogenic pSmad3L. PD98059 blocked pSmad2L but had no effect on elevated pSmad2C and oncogenic pSmad3L. All but PD98059 blocked Smad2/3/4 complex formation and restored Smad7 expression, while all the three MAPK-Specific inhibitors repressed PAI-1 mRNA transcription. Both SP600125 and SB203580 inhibited HepG2 cells’ proliferation and invasion by blocking oncogenic pSmad3L and Smad2/3/4 complex formation. PD98059 repressed PAI-1 mRNA by an unknown mechanism.


Hepatocellular carcinoma MAPK-specific inhibitors Smad TGF-β1 



This study was financially supported by the National Natural Science Foundation of China (no. 81073098, no. 81374012). We also thank Prof. K Matsuzaki, Department of Gastroenterology and Hepatology, Kansai Medical University, Osaka, Japan, for providing us the following Abs: anti-pSmad2L and anti-pSmad3L.

Conflicts of interest



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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Department of Pharmacology and Institute of Natural MedicineAnhui Medical UniversityHefeiChina
  2. 2.Department of AnesthesiologyThe Second Hospital of Anhui Medical UniversityHefeiChina

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