Alterations in TGF-β signaling leads to high HMGA2 levels potentially through modulation of PJA1/SMAD3 in HCC cells
Kazufumi Ohshiro1, Jian Chen2, Jigisha Srivastav3, Lopa Mishra1,4 and Bibhuti Mishra1
1 Department of Surgery, Center for Translational Medicine, George Washington University, Washington DC, USA
2 Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
3 University of Toledo College of Medicine, Toledo, OH, USA
4 Department of Gastroenterology and Hepatology, VA Medical Center, Washington DC, USA
Correspondence:
Lopa Mishra, email:
Keywords: TGF-β pathway, HMGA2, PJA1, Hepatocellular carcinoma
Received: October 07, 2019 Accepted: January 06, 2020 Published: January 22, 2020
Abstract
Recently, we observed that the TGF-β pathway is altered in 39% of HCCs. The alterations are correlated with a raised HMGA2 level. Therefore, we compared genetic alterations of HMGA2 and 43 TGF-β pathway core genes in HCC patients from TCGA database. Genetic alterations of 15 genes, including INHBE, INHBC, GDF11, ACVRL and TGFB2 out of 43 core genes, highly-moderately matched that of HMGA2. Co-occurrences of mutation amplification, gains, deletions and high/low mRNA of HMGA2 with those of the core genes were highly significant in INHBE, INHBC, ACVR1B, ACVRL and GDF11. Mass spectrometry studies revealed that HMGA2 interacted with an E3 ligase, PJA1, and that this interaction is enhanced by TGF-β treatment in the nuclear of HCC cells. Co-localization of nuclear PJA1 and HMGA2 in HCC cells increased upon TGF-β treatment. Raised HMGA2 levels that occur with alterations in the TGF-β signaling pathway may reflect an altered activity of E3 ligases, such as PJA1, and potentially contribute to the tumor-promoting roles of TGF-β signaling. Here, we report that the co-occurrence of genetic alterations in HMGA2 and TGF-β pathway core genes is implicated in HCC progression, and propose that HMGA2 and PJA1 may be potential novel targets in dysfunctional TGF-β signaling in HCC.
