KITENIN Is Associated With Activation of AP-1 Target Genes via MAPK Cascades Signaling in Human Hepatocellular Carcinoma Progression

Abstract

KITENIN promotes cancer cell migration and invasion in vitro and cancer metastasis in mouse cancer models, including colon and head and neck cancers. The purposes of this study were to observe the effect of KITENIN on tumor cell behaviors of human hepatocellular carcinoma (HCC) cells and to evaluate its expression in human HCC tissues. To functionally characterize KITENIN in human HCC, we depleted its expression in human HCC cell lines, HepG2 and Huh7, by using small interfering RNA (siRNA). Invasion and proliferation assays were performed. The activator protein-1 (AP-1) transcriptional activity and expression of AP-1 target genes were evaluated by AP-1 luciferase reporter assay and RT-PCR. The contribution of mitogen-activated protein kinase (MAPK) cascade signaling involved in AP-1 activation was assessed by Western blotting. We evaluated the expression of KITENIN and AP-1 target genes at mRNA levels by RT-PCR in human HCC tissues and paired normal hepatic mucosa of the same patients taken by surgery. Knockdown of KITENIN in HepG2 and Huh7 cells resulted in a significant reduction of tumor cell invasion. The tumor cell proliferation was significantly decreased in the KITENIN knocked down Huh7 cells compared to the negative control. The mRNA expressions of MMP-3 and COX-2 were decreased in KITENIN knocked down Huh7 cells. The mRNA expression of MMP-1 was decreased in KITENIN knocked down HepG2 cells. The AP-1 transcriptional activity in Huh7 cells was significantly decreased by knockdown of KITENIN. The JNK and ERK1/2 phosphorylations were decreased in KITENIN knocked down HepG2 and the p38 phosphorylation was decreased in KITENIN knocked down Huh7 cells. The mRNA expressions of KITENIN, MMP-1, and MMP-3 were significantly upregulated in human HCC tissues compared to paired normal mucosa. These results indicate that KITENIN is associated with activation of AP-1 target genes via MAPK cascades signaling in human HCC progression.

Stage of Breast Cancer Progression Influences Cellular Response to Activation of the WNT/Planar Cell Polarity Pathway

“…We have previously shown that expression of VANGL1 is increased with malignancy of the 21T series cells7, although a potential functional role for VANGL1/PCP pathway in this system has yet to be explored. According to recent reports, downregulation of VANGL1 expression inhibits progression of hepatocellular carcinoma cells18, and this has been shown to be associated with decreased expression of AP-1 target genes such as COX-2 and MMP319. VANGL1 has also been shown to bind to the metastasis suppressor KAI1/CD82 in the mouse colon cancer cell line CT-26, increasing invasiveness and adhesion to fibronectin in vitro and increasing tumorigenicity and metastasis in vivo20.…”

Elevated Coexpression of KITENIN and the ErbB4 CYT-2 Isoform Promotes the Transition from Colon Adenoma to Carcinoma Following APC loss

“…KITENIN participates in the dissemination of colorectal (14), head and neck squamous (15,16), gastric (17), and hepatocellular cancer cells (18). We observed a tumor-regressive effect of KITENIN siRNA when introduced intravenously in a mouse colon tumor model (19,20).…”

An Unconventional KITENIN/ErbB4-Mediated Downstream Signal of EGF Upregulates c-Jun and the Invasiveness of Colorectal Cancer Cells

“…KITENIN protein expression is significantly higher in human colon (11,12), laryngeal (14), oral cavity squamous (15), gastric (16), and hepatocellular (17) cancer tissues than in corresponding normal mucosa or early-stage cancer tissues. Interaction of KITENIN with Dishevelled (Dvl)/PKCd is important in regulating colorectal cancer cell invasion via ERK/AP-1 activation (11) and expression of KITENIN is significantly associated with lymph node metastasis and poor survival of colorectal cancer (12).…”

“…Previously, we identified KAI1 C-terminal interacting tetraspanin (KITENIN) as a metastasis-enhancing gene (9,10) that participates in the dissemination of colorectal (11,12), squamous (13)(14)(15), gastric (16), and hepatocellular cancer cells (17). KITENIN protein expression is significantly higher in human colon (11,12), laryngeal (14), oral cavity squamous (15), gastric (16), and hepatocellular (17) cancer tissues than in corresponding normal mucosa or early-stage cancer tissues.…”