Tspan8 Is Highly Expressed in Clear Cell Renal Cell Carcinoma and Indicates Poor Prognosis.

OBJECTIVE: Tspan8 (tetraspanin 8) plays critical roles in cell adhesion and motility. Recently, Tspan8 overexpression has been found in various tumors. However, its expression status and prognostic significance in clear cell renal cell carcinoma (ccRCC) remains unknown. The objective of the present study was to assess the expression of Tspan8 and its correlation with clinicopathological features in ccRCC. METHODS: Tspan8 expression was detected in 150 cases of ccRCC and matched paracancerous tissues by immunohistochemistry (IHC) and its relevance with prognosis was analyzed. RESULTS: Our data showed that the high-expression rate of Tspan8 in ccRCC tissues was 74.0%, which was significantly higher than those in paracancerous kidney tissues (43.3%, P=0.001). Meanwhile, Tspan8 expression was positively correlated with tumor size and WHO/ISUP grade in ccRCC. Significantly, Kaplan-Meier analysis and log-rank test revealed that Tspan8 higher expression was associated with poorer overall survival (OS) in ccRCC patients (P<0.05). Cox regression analysis further showed that Tspan8 was a significant independent negative prognostic factor for these patients. CONCLUSION: Tspan8 is overexpressed in ccRCC and indicates poor prognosis, suggesting potential roles of Tspan8 in prognostication and targeted therapy.

Vaginal Low-Grade Endometrial Stromal Sarcoma: An Extremely Rare Case Report and Review of the Literature.

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.

Prevalence and Genotype Distribution of High-Risk Human Papillomavirus among Chinese Women in Sichuan Province.

The estimation of prevalence and genotype distribution of high-risk human papillomavirus (HR-HPV) is important in formulating strategies for the prevention and screening of cervical cancer. This study aimed to determine HR-HPV prevalence and genotype distribution among Chinese women living in Sichuan Province. A total of 3,089 women were recruited from the Third People's Hospital of Chengdu in Sichuan Province. HR-HPV genotyping was assessed using real-time quantitative polymerase chain reaction. Up to 720 women (23.3%) were HR-HPV positive. A total of 81.1% (584/720) of women had a single HR-HPV genotype, and 18.9% (136/720) had multiple genotypes. The most frequently detected HPV genotype was HPV52, followed by HPV58, HPV16, and HPV51. Age subgroup analysis showed 2 peaks for the frequencies of HPV infections, one for the group of women under 29 years old, and the other for the group of women over 50 years old. Among the women for whom cytology results were available, HPV16 was the most commonly detected genotype among women affected with high-grade squamous intraepithelial lesion (32.5%) and squamous cell carcinoma, followed by HPV58, HPV33, and HPV52. This is one of the largest studies to demonstrate HPV prevalence and genotype distribution among Chinese women in Sichuan. The prevalence and genotype distribution of HR-HPV was unique with higher frequencies of HPV52 and HPV58.

Ataxia-telangiectasia group D complementing gene (ATDC) promotes lung cancer cell proliferation by activating NF-κB pathway.

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/ß-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.

Leucine zipper tumor suppressor 2 inhibits cell proliferation and regulates Lef/Tcf-dependent transcription through Akt/GSK3ß signaling pathway in lung cancer.

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 GSK3ß and ß-catenin through inactivating the Akt pathway. These results provide novel mechanistic insight into the biological roles of LZTS2 in lung cancer cells.

Ataxia-telangiectasia group D complementing gene (ATDC) upregulates matrix metalloproteinase 9 (MMP-9) to promote lung cancer cell invasion by activating ERK and JNK pathways.

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.

Upregulation of δ-catenin is associated with poor prognosis and enhances transcriptional activity through Kaiso in non-small-cell lung cancer.

δ-Catenin is the only member of the p120 catenin (p120ctn) subfamily that its primary expression is restricted to the brain. Since δ-catenin is upregulated in human lung cancer, the effects of δ-catenin overexpression in lung cancer still need to be clarified. Immunohistochemistry was performed to investigate the expression of δ-catenin and Kaiso, a δ-catenin-binding transcription factor, in 151 lung cancer specimens. A correlation between cytoplasmic δ-catenin and Kaiso expression was also associated with high TNM stage, lymph node metastases and poor prognosis. Co-immunoprecipitation assay confirmed the interactions of δ-catenin and Kaiso in lung cancer cells. In addition, gene transfection and RNAi technology were used to demonstrate that increased δ-catenin expression was promoted, whereas its knockdown suppressed its lung cancer invasive ability. In addition, methylation-specific PCR and ChIP assay demonstrated that δ-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 δ-catenin/Kaiso pathway exists in lung cancer cells. Increased δ-catenin expression is critical for maintenance of the malignant phenotype of lung cancer, making δ-catenin a candidate target protein for future cancer therapeutics.

delta-Catenin promotes malignant phenotype of non-small cell lung cancer by non-competitive binding to E-cadherin with p120ctn in cytoplasm.

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.