Abstract
BackgroundHepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide owing to its high rates of metastasis and recurrence. The oncogene IQ motif-containing GTPase activating protein 3 (IQGAP3) is ubiquitously overexpressed in several human cancers, including liver, ovary, lung, large intestine, gastric, bone marrow, and breast malignancies and is involved in the invasion and metastasis of cancer cells. Therefore, we aimed to determine the biological role and molecular mechanism of IQGAP3 in HCC.MethodsWe used 120 archived clinical HCC samples, 9 snap-frozen HCC tumor tissues, and 4 normal liver tissues. Expression of IQGAP3 mRNA and protein in HCC cell lines (Hep3B, SMMC-7721, HCCC-9810, HepG2, BEL-7404, HCCLM3, QGY-7701, Huh7, and MHCC97H) and normal liver epithelial cells LO2 was examined by western blot, quantitative polymerase chain reaction, and immunohistochemistry. In addition, wound-healing and transwell matrix penetration assays were used to assess the migratory and invasive abilities of HCC cells, respectively.ResultsExpression of the IQGAP3 was robustly upregulated in HCC cells and tissues. High expression of IQGAP3 in HCC correlated with aggressive clinicopathological features and was an independent poor prognostic factor for overall survival. Furthermore, ectopic expression of IQGAP3 markedly enhanced HCC cell migration, invasion, and epithelial-to-mesenchymal transition (EMT) in vitro and promoted metastasis of orthotopic hepatic tumors in nude mice. Conversely, silencing endogenous IQGAP3 showed an opposite effect. Mechanistically, IQGAP3 promoted EMT and metastasis by activating TGF-β signaling.ConclusionsIQGAP3 functions as an important regulator of metastasis and EMT by constitutively activating the TGF-β signaling pathway in HCC. Our findings present new evidence of the role of IQGAP3 in EMT and metastasis, indicating its potential as a prognostic biomarker candidate and a therapeutic target against HCC.
Highlights
Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide owing to its high rates of metastasis and recurrence
IQ motif-containing GTPase activating protein 3 (IQGAP3) is upregulated in human HCC cell lines and tissues Analysis of the mRNA expression of IQGAP3 in HCC tissues showed that IQGAP3 levels remained low in nontumor liver tissues, but increased significantly in patients with HCC (P < 0.0001), suggesting that IQGAP3 might contribute to the high cell-proliferation rates in HCC (Fig. 1a)
Upregulation of IQGAP3 expression is correlated with poor prognosis and metastasis in HCC IQGAP3 expression of 120 paraffin-embedded HCC tissues was examined by IHC
Summary
Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide owing to its high rates of metastasis and recurrence. Human hepatocellular carcinoma (HCC), one of the most common primary malignancies of the liver, is the thirdleading cause of cancer mortality worldwide and the. A transient phenomenon involved in the metastasis of various types of cancers is epithelial-to-mesenchymal transition (EMT), which plays a key role in the invasion. Emerging evidence suggests that EMT contributes to tumor metastasis and recurrence of various cancers including HCC. When TGF-β signaling is activated, cancer cells acquire access to the EMT program, lose their epithelial characteristics including polarity and specialized cell–cell contacts, and acquire migratory capacity, allowing them to invade the surrounding tissues, lymphatic and blood vessels, and even remote locations [13,14,15]. TGF-β signaling-associated induction of the EMT is considered a key step in the progression of tumor metastasis
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