Overexpression of p62/IMP2 can Promote Cell Migration in Hepatocellular Carcinoma via Activation of the Wnt/β-Catenin Pathway

Abstract

p62/IMP2 is an oncofetal protein that was first reported as a tumor-associated antigen in hepatocellular carcinoma (HCC). In our previous studies, we demonstrated a high frequency of p62/IMP2 autoantibodies appearing in various types of cancer. Therefore, we hypothesize that p62/IMP2 plays an important role in the progression of HCC, although the mechanism remains to be explored. In this study, we evaluated the expression of p62/IMP2 protein both in human tissues and liver cancer cell lines by immunohistochemistry and western blotting analysis and found that p62/IMP2 protein is overexpressed in human HCC tissue in comparison to normal human liver tissue. To explore the role that p62/IMP2 plays in HCC, p62/IMP2 was knocked out in two p62/IMP2-positive liver cancer cell lines (SNU449 and HepG2). Due to the low expression level of p62/IMP2 in SNU449, we overexpressed p62/IMP2 in this cell line. We subsequently demonstrated that high expression of p62/IMP2 in both cell lines can promote cell migration and invasion abilities in vitro by activating the Wnt/β-catenin pathway. We also used the Wnt/β-catenin pathway inhibitor, XAV 939, and a phosphoproteome assay to confirm our findings. Conclusion: Our results suggest that p62/IMP2 is an essential regulator of Wnt signaling pathways and plays an important role in HCC progression and metastasis.Cancers 2020, 12, 7 2 of 16 with various mRNA to regulate their stability, translatability, and localization [9]. IMPs are considered oncofetal proteins, and their overexpression in various types of cancers has been reported [8,9]. p62/IMP2 was originally reported as a tumor-associated antigen (TAA) in HCC [10]. The high frequency of anti-p62/IMP2 autoantibody occurrence in the serum samples from various types of cancer patients implies that p62/IMP2 may play a role in cancer progression [11][12][13][14]. Several cancer-associated p62/IMP2 target mRNAs have been identified. They include CCN2 mRNA [15], IGF2 mRNA [7], and c-Myc mRNA [15]. Some studies have reported that p62/IMP2 is involved in carcinogenesis. When phosphorylated by mTOR, p62/IMP2 stabilizes HMGA1 and stimulates the expression of IGF2, potentially leading to increased cancer cell proliferation [16]. By activating the IGF2/PI3K/Akt pathway, p62/IMP2 can conceivably promote proliferation, migration, invasion, and epithelial to mesenchymal transition (EMT) of glioblastoma cells [17]. Recently, p62/IMP2 has been shown to enhance the migration ability of cancer cells and promote cancer metastasis. A cluster of p62/IMP2 targets (LIMS2, TRIM54, and LAMB2) are considered to be involved in the downstream effects of p62/IMP2 expression that indeed increased cell migration, cell adhesion, and cytoskeleton remodeling, which can promote the metastatic behavior of cancer cells [18]. A recent study from our group demonstrated that the overexpressed p62/IMP2 enhances the expression of β-catenin and CTGF, which therefore heightens cell migration and reduces cell adhesion in breast cancer cells [15]. Another group also reported that p...

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