As a member of the catenin family, little is known about the clinical significance and possible mechanism of delta-catenin expression in numerous tumours. We examined the expression of delta-catenin by immunohistochemistry in 115 cases of non-small cell lung cancer (NSCLC) (including 65 cases with follow-up records and 50 cases with paired lymph node metastasis lesions). The mRNA and protein expression of delta-catenin was also detected in 30 cases of paired lung cancer tissues and normal lung tissues by RT-PCR and western blotting, respectively. Co-immunoprecipitation was used to examine whether delta-catenin competitively bound to E-cadherin with p120ctn in lung cancer cells or not. The effects of delta-catenin on the activity of small GTPases and the biological behaviour of lung cancer cells were explored by pull-down assay, flow cytometry, MTT, and Matrigel invasive assay. The results showed that the mRNA and protein expression of delta-catenin was increased in lung cancer tissues; the positive expression rate of delta-catenin was significantly increased in adenocarcinoma, stage III-IV, paired lymph node metastasis lesions, and primary tumours with lymph node metastasis (all p < 0.05); and the postoperative survival period of patients with delta-catenin-positive expression was shorter than that of patients with delta-catenin-negative expression (p < 0.05). No competition between delta-catenin and p120ctn for binding to E-cadherin in cytoplasm was found in two lung cancer cell lines. By regulating the activity of small GTPases and changing the cell cycle, delta-catenin could promote the proliferation and invasion of lung cancer cells. We conclude that delta-catenin is an oncoprotein overexpressed in NSCLC and that increased delta-catenin expression is critical for maintenance of the malignant phenotype of lung cancer.

d-Catenin is the only member of the p120 catenin (p120ctn) subfamily that its primary expression is restricted to the brain. Since d-catenin is upregulated in human lung cancer, the effects of d-catenin overexpression in lung cancer still need to be clarified. Immunohistochemistry was performed to investigate the expression of d-catenin and Kaiso, a d-catenin-binding transcription factor, in 151 lung cancer specimens. A correlation between cytoplasmic d-catenin and Kaiso expression was also associated with high TNM stage, lymph node metastases and poor prognosis. Co-immunoprecipitation assay confirmed the interactions of d-catenin and Kaiso in lung cancer cells. In addition, gene transfection and RNAi technology were used to demonstrate that increased d-catenin expression was promoted, whereas its knockdown suppressed its lung cancer invasive ability. In addition, methylation-specific PCR and ChIP assay demonstrated that d-catenin could regulate MTA2 via Kaiso in a methylation-dependent manner, while it could regulate cyclin D1 and MMP7 expression through Kaiso in a sequence-specific manner. In conclusion, a d-catenin ⁄ Kaiso pathway exists in lung cancer cells. Increased d-catenin expression is critical for maintenance of the malignant phenotype of lung cancer, making d-catenin a candidate target protein for future cancer therapeutics. (Cancer Sci 2011; 102: 95-103) p 120 catenin (p120ctn) plays an important role in tumor progression and metastasis of non-small-cell lung cancer (NSCLC).(1,2) It is an Armadillo protein, which was first identified as a tyrosine kinase substrate implicated in cell transformation by Src.(3) It can bind to the juxtamembrane domain (JMD) of E-cadherin (4,5) where it modulates cell-cell adhesion by regulating cadherin turnover and stability at the cell surface.(6-8) In addition, p120ctn can bind directly with Kaiso, a transcription factor, (9) implicating a role for p120ctn in the regulation of transcriptional activity in addition to its cell-cell adhesion function.As a binding factor of p120ctn, Kaiso is a member of the BTB ⁄ POZ (Broad complex, Tramtrak, Bric à brac ⁄ Pox virus and zinc finger) subfamily of zinc finger proteins. It has the characteristic POZ domain at its amino-terminus where it facilitates Kaiso homodimerization and heterodimerization with diverse proteins, (10) while the zinc finger domain at the carboxyl terminal of Kaiso is responsible for DNA association.(11) Unlike any of the previously characterized POZ proteins, Kaiso could recognize both sequence-specific DNA consensus (KBS, TCCTGCNA) and methylated CpG-dinucleotides.(12,13) As a transcription repressor, (14) the majority of candidate Kaiso target genes identified thus far, that is, CDH1 (E-cadherin), MMP7, MTA2 and Wnt11, have been linked with development and ⁄ or cancer. (15) d-Catenin is an adhesive junction associated protein, (16,17) which is the only member of the p120ctn subfamily and its primary expression is restricted to the brain. Initially, it was widely accepted that d-catenin is the only m...

Previous studies suggested Ataxia-telangiectasia group D complementing gene (ATDC) as an oncogene in many types of cancer. However, its expression and biological functions in non-small cell lung cancer (NSCLC) remain unclear. Herein, we investigated its expression pattern in 109 cases of human NSCLC samples by immunohistochemistry and found that ATDC was overexpressed in 62 of 109 NSCLC samples (56.88%). ATDC overexpression correlated with histological type (p<0.0001), tumor status (p = 0.0227) and histological differentiation (p = 0.0002). Next, we overexpressed ATDC in normal human bronchial epithelial cell line HBE and depleted its expression in NSCLC cell lines A549 and H1299. MTT and colony formation assay showed that ATDC overexpression promoted cell proliferation while its depletion inhibited cell growth. Furthermore, cell cycle analysis showed that ATDC overexpression decreased the percentage of cells in G1 phase and increased the percentage of cells in S phase, while ATDC siRNA treatment increased the G1 phase percentage and decreased the S phase percentage. Further study revealed that ATDC overexpression could up-regulate cyclin D1 and c-Myc expression in HBE cells while its depletion down-regulated cyclin D1 and c-Myc expression in A549 and H1299 cells. In addition, ATDC overexpression was also associated with an increased proliferation index, cyclin D1 and c-Myc expression in human NSCLC samples. Further experiments demonstrated that ATDC up-regulated cyclin D1 and c-Myc expression independent of wnt/β-catenin or p53 signaling pathway. Interestingly, ATDC overexpression increased NF-κB reporter luciferase activity and p-IκB protein level. Correspondingly, NF-κB inhibitor blocked the effect of ATDC on up-regulation of cyclin D1 and c-Myc. In conclusion, we demonstrated that ATDC could promote lung cancer proliferation through NF-κB induced up-regulation of cyclin D1 and c-Myc.

Although the expression pattern and biological functions of ataxia-telangiectasia group D complementing gene (ATDC) had been implicated in several types of cancer, the roles and potential mechanisms of ATDC in lung cancer cell invasion are still ambiguous. In this study, we used gain- and loss-of-function analyses to explore the roles and potential mechanisms of ATDC in lung cancer cell invasion. siRNA knockdown of ATDC impaired cell invasion in A549 and H1299 cell lines, and its overexpression promoted cell invasion in HBE cell line. ATDC may contribute to the invasive ability of lung cancer cells by promoting the expression of invasion-related matrix metalloproteinase 9 (MMP-9). In addition, ATDC increased activating protein 1 (AP-1) reporter luciferase activity and the protein and mRNA levels of c-Jun and c-Fos. We further demonstrated that the roles of ATDC on cell invasion, MMP-9 upregulation, and AP-1 activation were dependent on extracellular signal-regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) pathway activation, and ERK inhibitor U0126 or JNK inhibitor SP600125 blocked these effects of ATDC. These results suggested that ATDC upregulates MMP-9 to promote lung cancer cell invasion by activating ERK and JNK pathways.

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Leucine zipper tumor suppressor 2 (LZTS2) is implicated in several cancers; however, its biological mechanisms in non-small cell lung cancer (NSCLC) are not yet understood. We found that low levels of LZTS2 in NSCLC were correlated with tumor and nodal status. LZTS2 could inhibit cell proliferation and cell cycle transition at the G1/S phase and was implicated in the regulation of proteins associated with the canonical Wnt pathway, including GSK3β and β-catenin through inactivating the Akt pathway. These results provide novel mechanistic insight into the biological roles of LZTS2 in lung cancer cells.

Endometrial stromal sarcoma (ESS) is a malignant tumor of the uterus that has been described as the second most common malignant uterine mesenchymal tumor. Primary extrauterine ESS (EESS) is an extremely uncommon occurrence. We hereby report a new bona fide case of low-grade EESS in a 74-yr-old woman arising in the vagina, presenting as a polypoid mass associated with irregular vaginal bleeding. On examination, a 6×2×2 cm polypoid mass was found in the left vaginal wall. Consequently, the patient underwent partial vaginectomy and repair. No ESS or endometriotic lesion was found in the endometrium and bilateral adnexa. The diagnosis of ESS performed by typical pathologic and immunohistochemical evaluation was as follows: beta-catenin (+++), estrogen receptor (+++), progesterone receptor (++), vimentin (++), and uniformly negative for CD10, EMA, CD31, CD34, CD117,CD99, SMA, desmin, h-caldesmon, S-100, MelanA, and HMB45. She has remained disease free with no signs or symptoms of recurrent or advanced disease for 46 mo. Although CD10 is the most useful immunohistochemical marker for the diagnosis of this tumor, negative CD10 staining can be encountered with underfixation. Therefore, it is important to use a panel of immunostains that includes CD10, beta-catenin, and smooth muscle markers. The present study describes the clinical and pathologic features of low-grade EESS through a case report and literature review. To the best of our knowledge, this is the eighth report of EESS arising from the vagina.

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