1015

CDH17

cadherin 17, LI cadherin (liver-intestine);CDH17;cadherin 17, LI cadherin (liver-intestine)

HPT-1 cadherin|LI cadherin|LI-cadherin|cadherin-16|cadherin-17|human intestinal peptide-associated transporter HPT-1|human peptide transporter 1|intestinal peptide-associated transporter HPT-1|liver-intestine cadherin

8q22.1

protein-coding

Liver-intestine cadherin (LI-cadherin) is a recently identified member of the cadherin superfamily. We examined LI-cadherin expression in four human colorectal carcinoma cell lines and 45 human primary colorectal carcinomas using a monoclonal antibody against LI-cadherin. We also investigated the correlation between LI-cadherin expression and clinicopathologic parameters. Among the cell lines, LI-cadherin expression was detected in a differentiated phenotype, but not in dedifferentiated phenotypes. Among the 45 tumor samples, LI-cadherin expression was preserved in 28 (62%) and reduced in 17 (38%). Reduced LI-cadherin expression was significantly associated with a high tumor grade (P = 0.015), lymphatic invasion (P = 0.033), lymph node metastasis (P = 0.015), and an advanced pTNM stage (P = 0.033). These results suggest that analysis of LI-cadherin expression may help to indicate the biological aggressiveness of this malignancy.

PURPOSE: The aim of this study was to investigate the role of Li-cadherin in invasion and metastasis in LoVo cells. METHODS: We applied RNA interference mediated downregulation of Li-cadherin expression in LoVo cells. Li-cadherin expression in LoVo cells was examined by semiquantitative polymerase chain reaction, immunofluorescence, western blot, and immunoprecipitation, respectively. Effect of suppression of Li-cadherin expression on cell migration, invasion, and adhesion was detected by wound healing assay, migration assay, invasion assay, and adhesion assay. expression and activity of MMP-2 and MMP-9 were analyzed by gelatin zymography. RESULTS: Cell migration, invasion, and adhesion were increased concomitantly with the reduction in Li-cadherin protein expression. Furthermore, downregulation of Li-cadherin expression induced secretion of proMMP-9, active MMP-9 and active MMP-2. CONCLUSIONS: This study suggests that silencing Li-cadherin has positive actions in the processes of LoVo cells invasion and metastasis, and the interactions among MMP-2, MMP-9, and Li-cadherin participate in the multiple steps of invasion and metastasis in LoVo colorectal cancer cells.

Human telomerase reverse transcriptase (hTERT) is the catalytic subunit of human telomerase and its rate-limiting component. The purpose of the present study was to investigate the diagnostic value of hTERT in serum of cervical cancer patients. Preoperative values of hTERT, squamous cell carcinoma antigen (SCC-ag) and cancer antigen 125 (CA 125) were measured by enzyme-linked immunosorbent assay (ELISA) in 192 patients with squamous cell carcinoma or adenocarcinoma of the uterine cervix and 38 healthy controls. Elevated pretreatment levels of hTERT were identified in 80.2% of squamous cell carcinoma and 73.8% of adenocarcinoma patients. The expression of serum hTERT was correlated with telomerase activity in cancer tissues of both histological types. Pretreatment serum hTERT levels showed a significant correlation with clinical stage, tumor size and lymph node metastasis, but not with age. Serum hTERT measurement was found to be useful in the diagnosis and assessment of clinical stage of cervical cancer, and to be superior to the conventional tumor markers. Therefore, serum hTERT is a novel and readily available marker for cervical malignancies.

Liver metastasis is the major cause of death associated to colorectal cancer. Cadherin-17 (CDH17) is a non-classical, seven domain, cadherin lacking the conserved cytoplasmic domain of classical cadherins. CDH17 was overexpressed in highly metastatic human KM12SM and present in many other colorectal cancer cells. Using tissue microarrays, we observed a significant association between high expression of CDH17 with liver metastasis and poor survival of the patients. On the basis of these findings, we decided to study cellular functions and signaling mechanisms mediated by CDH17 in cancer cells. In this report, loss-of-function experiments demonstrated that CDH17 caused a significant increase in KM12SM cell adhesion and proliferation. Coimmunoprecipitation experiments demonstrated an interaction between CDH17 and alpha2beta1 integrin with a direct effect on beta1 integrin activation and talin recruitment. The formation of this complex, together with other proteins, was confirmed by mass spectrometry analysis. CDH17 modulated integrin activation and signaling to induce specific focal adhesion kinase and Ras activation, which led to the activation of extracellular signal-regulated kinase and Jun N-terminal kinase and the increase in cyclin D1 and proliferation. In vivo experiments showed that CDH17 silencing in KM12 cells suppressed tumor growth and liver metastasis after subcutaneous or intrasplenic inoculation in nude mice. Collectively, our data reveal a new function for CDH17, which is to regulate alpha2beta1 integrin signaling in cell adhesion and proliferation in colon cancer cells for liver metastasis.

Gastric cancer remains the second leading cause of cancer deaths worldwide. Patients usually present late with local invasion or metastatic diseases. The present study investigated the expression level of liver-intestine cadherin (LI-cadherin) by RT-PCR and its correlation with clinicopathological data in 71 pairs of tumor and non-cancerous gastric mucosa. Protein expression level of LI-cadherin was determined by Western blotting and immunohistochemistry. The mRNA of LI-cadherin was highly expressed in tumor as compared to non-cancerous mucosa. Lymph node metastasis was significantly associated with the expression of LI-cadherin (p=0.038). On multivariate analysis, T staging and LI-cadherin expression were found to be independent factors associated with lymph node metastasis.

Cadherin-17 (CDH17), as a structurally unique member of the cadherin superfamily, has been identified to predict a poor prognosis for gastric cancer (GC). Our previous study demonstrated the positive correlation between CDH17 and lymph node micrometastasis in GC. We sought to further identify the role of CDH17 in the tumorigenesis and lymphatic metastasis of GC. Hence, we inhibited the CDH17 expression in MKN-45 gastric cancer cells by using RNA interference. Consequently, the malignant potency of cancer cells was evaluated, and the change in NFkappaB signaling pathway was also probed. tumor growth and lymphatic metastasis model were conducted in nude mice to confirm the hypothesis. Downregulation of CDH17 not only suppressed the proliferation, adherence and invasion potency of MKN-45 cells, but also induced cell cycle arrest. Meanwhile, the NFkappaB signaling pathway was inactivated as well, with the reductions of downstream proteins including VEGF-C and MMP-9. Moreover, silencing CDH17 inhibited tumor growth in vivo significantly, and there was no lymph node metastasis detected in the mice without CDH17 expression, as opposed to the positive nodes found in controls. CDH17 is a novel oncogene in gastric cancer cells, which is associated with lymphatic metastasis and proliferation strongly. The inactivation of NFkappaB signaling pathway might be involved in targeting CDH17 in GC. On the whole, CDH17 is proposed to serve as a biomarker and attractive therapeutic target in GC.