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

Abstract

Purpose and Experimental Design: The molecular events in the malignant progression of colon adenoma after loss of adenomatous polyposis coli (APC) are not fully understood. KITE-NIN (KAI1 C-terminal interacting tetraspanin) increases the invasiveness of colorectal cancer cells, and we identified a novel EGFRindependent oncogenic signal of EGF that works under coexpressed KITENIN and ErbB4. Here we tested whether elevated KITENIN and ErbB4 contribute to further progression of intestinal adenoma following APC loss.Results: The intestinal tissues of villin-KITENIN transgenic mice in which villin-driven KITENIN expression induces increased c-Jun expression exhibit mild epithelial cell proliferation but no epithelial lineage changes compared with those of nontransgenic mice. Among the four ErbB4 isoforms, JM-a/CYT-2 and JM-b/CYT-2 exhibited the highest AP-1 activity when cells coexpressing KITE-NIN and each isoform were stimulated by EGF. Interestingly, predominant overexpression of the ErB4-CYT-2 mRNA as well as increased EGFR expression were observed in intestinal adenoma of APC min/þ mice, which makes the microenvironment of activated EGF signaling. When we crossed villin-KITENIN mice with APC min/þ mice, intestinal tumor tissues in the crossed mice showed the characteristics of early-stage invading adenocarcinoma. In patients with colorectal cancer, ErbB4-CYT-2 mRNA expression was significantly greater in tumor tissues than in normal adjacent tissues, but no significant differences in tumor tissue expression were found between different colorectal cancer stages. Furthermore, the mRNA expression of KITENIN and that of ErbB4-CYT-2 were positively correlated in human colorectal cancer tissue.Conclusions: Elevated coexpression of KITENIN and ErbB4-CYT-2 promotes the transition of colon adenoma to adenocarcinoma within an APC loss-associated tumor microenvironment.

HER4 isoform CYT2 and its ligand NRG1III are expressed at high levels in human colorectal cancer

“…A previous study found that the CYT2 variant, but not the CYT1 variant, protected EGFR from ligand-induced degradation by competing with EGFR for binding to a complex containing the E3 ubiquitin ligase c-Cbl and the adaptor Grb2 (22). In addition, another study showed that the ErbB4 CYT2 isoform promoted the transition from colon adenoma to carcinoma following adenomatous polyposis coli loss (23). However, another study demonstrated that the CYT2 isoform had an inhibitory effect on cancer cell growth (24).…”

Linc00152 Functions as a Competing Endogenous RNA to Confer Oxaliplatin Resistance and Holds Prognostic Values in Colon Cancer

“…43,44 Moreover, it has been considered to mediate acquired resistance to chemotherapy. 36 Consistently, we found that inhibition of ERBB4 enhanced colon cancer cells apoptosis in response to L-OHP.…”

KITENIN functions as a fine regulator of ErbB4 expression level in colorectal cancer via protection of ErbB4 from E3‐ligase Nrdp1‐mediated degradation

“…From these results, it is suggested that the greater elevation of KITENIN in stage IV CRC tissues could contribute to greater expression of ErbB4 in these tissues via protection of KITENIN‐bound ErbB4 from Nrdp1‐mediated degradation. Therefore, these results show that the functional significance of the KITENIN/ErbB4‐Nrdp1‐Dvl2 complex as established in vitro also applies in the clinical situation.…”

“…The RT-PCR exponential phase was determined to be 30 cycles to allow for quantitative comparison of the various cDNAs developed from identical reactions on a GeneAmp PCR system (Eppendorf). Real-time PCR analysis of cDNA samples was performed with specific primers and fluorescent probes designed using Primer Express software (PE Biosystems) as described (29). The PCR primers (forward/reverse) used are as follows: Nrdp1,…”

“…We recently identified a novel EGFR-independent unconventional signal of EGF that works under co-expressed KITENIN and ErbB4 and enhances CRC cell motility [11]. This KITENIN/ ErbB4-mediated EGF signal plays an important role in colorectal carcinogenesis within an APC-lossassociated tumor microenvironment [29]. Moreover, compound villin-KITENIN-TG/APC min/þ mice manifest the characteristics of early-stage invading adenocarcinoma, which reiterates the importance of elevated expression of KITENIN and ErbB4-CYT-2 in CRC tissues.…”