Tumor Suppressor In Lung Cancer 1 Research Articles

Overexpression of a cell adhesion molecule, TSLC1, as a possible molecular marker for acute-type adult T-cell leukemia

AbstractAdult T-cell leukemia (ATL) caused by human T-cell leukemia virus type 1 (HTLV-1) infection, occurs in 2% to 4% of the HTLV-1 carriers with a long latent period, suggesting that additional alterations participate in the development of ATL. To characterize and identify novel markers of ATL, we examined the expression profiles of more than 12 000 genes in 8 cases of acute-type ATL using microarray. One hundred ninety-two genes containing interleukin 2 (IL-2) receptor α were up-regulated more than 2-fold compared with CD4+ and CD4+CD45RO+ T cells, and tumor suppressor in lung cancer 1 (TSLC1), caveolin 1, and prostaglandin D2 synthase showed increased expression of more than 30-fold. TSLC1 is a cell adhesion molecule originally identified as a tumor suppressor in the lung but lacks its expression in normal or activated T cells. We confirmed ectopic expression of the TSLC1 in all acute-type ATL cells and in 7 of 10 ATL- or HTLV-1–infected T-cell lines. Introduction of TSLC1 into a human ATL cell line ED enhanced both self-aggregation and adhesion ability to vascular endothelial cells. These results suggested that the ectopic expression of TSLC1 could provide a novel marker for acute-type ATL and may participate in tissue invasion, a characteristic feature of the malignant ATL cells.

MicroRNA-873 Promotes Cell Proliferation, Migration, and Invasion by Directly Targeting TSLC1 in Hepatocellular Carcinoma

Background/Aims: Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and has the third highest mortality rate among all cancers. MicroRNAs are a class of endogenous, single-stranded short noncoding RNAs. The purpose of this study was to study the role of microRNA-873 in HCC. Methods: The expression of miRNA-873 and tumor suppressor in lung cancer 1 (TSLC1) in HCC tissues and cell lines was detected by real-time quantitative RT-PCR (RT-qPCR) or western blot. A CCK-8 assay was used to examine cell proliferation; flow cytometry was used to assess the cell cycle; the Transwell migration assay was used to test for metastasis. Luciferase assays were performed to assess whether TSLC1 was a novel target of miRNA-873. Results: We showed that miRNA-873 was upregulated in HCC tissues and cell lines compared with the normal control. Knockdown of miRNA-873 inhibited the growth and metastasis of HepG2 and accelerated G1 phase arrest, while overexpression of miRNA-873 had the opposite effect. The dual-luciferase reporter assays revealed that TSLC1 was a novel target of miRNA-873. Further study showed that TSLC1 was decreased in HCC tissues and cell lines. There was a negative correlation between the expression levels of TSLC1 and miRNA-873. The effect of miRNA-873 overexpression was neutralized by TSLC1. We also found that miRNA-873 activated the PI3K/AKT/mTOR signaling pathway and promoted HCC. Conclusions: Our data demonstrated that miRNA-873 promoted HCC progression by targeting TSLC1 and provided a new target for the therapy of HCC.

Down-regulation of long noncoding RNA RP11-713B9.1 contributes to the cell viability in non‑small cell lung cancer (NSCLC).

Early diagnosis is essential to reduce lung cancer-associated morbidity and mortality rates; however the lack of diagnostic biomarkers for lung cancer has made this difficult. Recent studies have demonstrated that long noncoding RNAs (lncRNAs) serve important roles in cancer occurrence and progression. The present study investigated the novel lncRNA RP11‑713B9.1, which is the antisense transcript of tumor suppressor in lung cancer 1 (TSLC1). The expression levels of RP11‑713B9.1 and TSLC1 in non‑small cell lung cancer were determined using reverse‑transcription quantitative polymerase chain reaction, which revealed that the expression of RP11‑713B9.1 and TSLC1 was significantly downregulated in tumor tissue compared with that in adjacent normal tissue samples. In addition, the expression of RP11‑713B9.1 was identified to be positively correlated with the expression of tumor suppressors TSLC1, CYLD lysine 63 deubiquitinase and APC WNT signaling pathway regulator, and negatively correlated with B‑Raf proto‑oncogene serine/threonine kinase expression. Furthermore, the overexpression of RP11‑713B9.1 resulted in significant upregulation of TSLC1 and inhibition of H460 cell viability, while the opposite effects were observed following the knockdown of RP11‑713B9.1 in A549 cells. Taken together, the results of the current study suggest that lncRNA RP11‑713B9.1 serves as a promising biomarker and potential therapeutic target for non‑small cell lung cancer.

AB179. Tumor suppressor in lung cancer-1 is a prognostic predictor for the recurrence and progression of non-muscle-invasive bladder cancer

ObjectiveTo investigate the relationship between tumor suppressor in lung cancer-1 (TSLC1) expression and clinicopathological characteristics and evaluate its prognostic significance in patients with non-muscle-invasive bladder cancer (NMIBC).MethodsTSLC1 expressions in 241 specimens of NMIBC were examined by immunohistochemistry. The correlation between TSLC1 expression and clinicopathological characteristics were evaluated by chi-square test. The prognostic significance of TSLC1 expression were analyzed by univariate, multivariate analysis and Kaplan-Meier survival curves.ResultsThe total negative rate of TSLC1 expression was 47.3% in NMIBC. Decreased expression of TSLC1 was correlated with higher clinical stage, higher pathological grade, more number of tumors, lager tumor size, tumor recurrence and progression. TSLC1 expression was an independent risk factor for predicting tumor recurrence (P=0.005)] and progression (P<0.001).ConclusionsTSLC1 expression in NMIBC tissues is correlated with tumor malignancy and may serves as a predicator for bladder cancer recurrence and progression.

Tumor suppressor in lung cancer 1 gene expression in epithelial ovarian cancer.

Loss of Tumor Suppressor in Lung Cancer 1(TSLC1) was observed in many different cancers, but there were only limited research on TSLC1 gene and its roles in cancer suppression in ovarian cancer. This study explores the relationship between TSLC1 gene expression and the ovarian epithelial cancer. Expression levels of TSLC1 were detected by immunohistochemical staining on formal-fixed paraffin embedded pathological specimen. A total of 259 samples were collected, including 24 benign ovarian tumor and 235 malignant ovarian cancers among them. Suppressed expression of TSLC1 protein was observed in 87.8% of poorly differentiated, 85.1% of moderately differentiated, and 46% of well differentiated ovarian epithelial cancers, respectively. There were none suppressed TSLC1 expression in benign ovarian tumor. Kruskal-Wallis test showed a significant association between the expression levels of TSLC1 gene and the degree of ovarian cancer differentiation (P < 0.001). Decreased expression of TSLC1 is associated with the differentiation in ovarian epithelial cancer. TSLC1 might be used as a molecular marker of severity in early stage ovarian cancer, and to help differentiating benign and malignant ovarian tumors.

Tumor Suppressor in Lung Cancer-1 Is a Prognostic Predictor for the Recurrence and Progression of Non-Muscle-Invasive Bladder Cancer

Objective: To investigate the relationship between the expression of tumor suppressor in lung cancer-1 (TSLC1) and clinicopathological characteristics of patients with non-muscle-invasive bladder cancer (NMIBC) and evaluate the prognostic significance of TSLC1. Methods: TSLC1 expression in 241 specimens of NMIBC was examined by immunohistochemistry. The correlation between TSLC1 expression and clinicopathological characteristics was evaluated using the chi-square test. The prognostic significance of TSLC1 was analyzed by univariate, multivariate analysis and Kaplan-Meier survival curves. Results: The total negative rate of TSLC1 expression was 47.3% in NMIBC. Decreased expression of TSLC1 was correlated with a higher clinical stage, higher pathological grade, the number of tumors, lager tumor size, tumor recurrence and progression. TSLC1 expression was an independent risk factor for predicting tumor recurrence (p = 0.005) and progression (p < 0.001). Conclusion: Decreased expression of TSLC1 is correlated with the malignancy of NMIBC tissues and low TSLC1 expression may serve as a predictor for bladder cancer recurrence and progression.

Significance of TSLC1 gene methylation and TSLC1 protein expression in the progression of cervical lesions

To study the expression and significance of tumor suppressor in lung cancer 1 (TSLC1) gene methylation, the expression of TSLC1 protein in cervix cancer and precancerous lesions as well as their relationship with HR-HPV DNA infection. The clinicopathological data of 92 cases of different cervical lesions during March 2011 to August 2012 treated in our hospital were collected. There were pathologically confirmed 10 cases of normal cervix, 26 cases of cervical intraepithelial neoplasia (CIN) I, 20 cases of CIN II, 15 cases of CIN III, and 21 cases of cervical cancer. Methylation-specific polymerase chain reaction (MSP) was used to detect the TSLC1 gene methylation status in cervical lesions, immunohistochemistry (SP) was used to detect the expressions of TSLC1 protein in cervical lesions, and the second generation hybrid capture (HC2) method was used to detect the high-risk HPV in cervical lesions. The expression rate of TSLC1 gene methylation in normal cervical tissue, CIN I, CIN II, CIN III and SCC were 10.0%, 30.8%, 55.0%, 60.0%, 66.7%, respectively, showing a statistically significant difference (P = 0.004). The positive expression rate of TSLC1 protein in normal cervical tissue, CIN I, CIN II, CIN III and SCC were 100.0%, 80.8%, 65.0%, 33.3%, and 23.8%, respectively, with a significant difference (P = 0.004). In the progression from CIN to invasive cervical cancer, there was no significant correlation between TSLC1 gene methylation and HR-HPV DNA infection (P = 0.919), TSLC1 protein expression and HR-HPV DNA infection (P = 0.664). The correlation analysis showed a negative correlation between TSLC1 gene methylation and TSLC1 protein expression (r = -0.674, P < 0.001). TSLC1 gene promoter methylation may be an early event in the cervical carcinogenesis, become an early sensitive marker, and serve the early prevention and prognostic prediction for cervical cancer.

Reduced tumor suppressor in lung cancer-1 expression is associated with a poor prognosis and its gene promoter methylation in colorectal adenocarcinoma

Objective To investigate the expression of tumor suppressor in lung cancer-1 (TSLC-1) and its gene promoter methylation in colorectal adenocarcinoma,and evaluate its clinical signifi-cance.Methods Immunohistochemical Envision two-step technique was used to detect the expression of TSLC1 in primary colorectal adenocarcinoma; and the relationships between the expression of TSLC1 and clinical parameter including prognosis were analysed statistically.The promoter methylation of TSLC1 gene was detected by methylation-specific polymerase chain reaction.Results TSLC-1 protein expressing positive rate in primary colorectal adenocarcinoma was 41.51％ (22/53),which was obviously lower than that in paraneoplastic colorectal mucous (100％,20/20).Compared with TSLC-1 positive expressing group,group of TSCL-1 negative expressing showed higher lymph node metastasis rate and more advanced clinical stage (P ＜ 0.05).The median survival time in TSLC-1 negative expressing group was 32.22 months,significantly shorter as compared with TSLC-1 positive expressing group (47.55 months) (P ＜ 0.05).TSLC-1 gene promoter region was methylated in 13 of 31 (41.94％) colorectal adenocarcinomas without TSLC-1 protein expressing,that was higher significantly than that in the group of TSLC-1 protein positive expressing (2/22) and normal tissue adjacent to cancer (1/20) (P ＜ 0.05).Conclusion TSLC-1 protein expression was down-regulated in primary colorectal adenocarcinoma,and it was an important factor for predicting prognosis; the methylation-mediated inactivation of TSLC-1 maybe is main mechanism of TSLC-1 expressing down-regulation. Key words: Colorectal adenocarcinama; Tumor suppressor in lung cancer-1; Gene methylation

Effect of tumor suppressor in lung cancer-1 on growth inhibition of MG63 cell line

Objective The aim of this study was to establish the osteosarcoma cell sublines which stably expressing tumor suppressor in lung cancer-1 (TSLC1) gene and evaluate its effect on growth inhibition of human osteosarcoma cell line MG63.

Tumor suppressor in lung cancer 1 (TSLC1), a novel tumor suppressor gene, is implicated in the regulation of proliferation, invasion, cell cycle, apoptosis, and tumorigenicity in cutaneous squamous cell carcinoma

Tumor suppressor in lung cancer 1 (TSLC1) is tightly implicated in a variety of biological processes and plays critical roles in tumor development and progression. However, the roles of TSLC1 in cutaneous squamous cell carcinoma (CSCC) remain to be unraveled. Here, we reported the TSLC1 gene that was significantly downregulated in CSCC tissues and cells, and survival times of patients with TSLC1 at a low level were markedly lower than that at a high level (P = 0.0070). A stepwise investigation demonstrated that an elevated TSLC1 level evoked obvious proliferation and invasion inhibitions and arrested cell cycle at G0/G1 phase in A431 cells. Moreover, increase of caspase-3 activity mediated by elevated TSLC1 level induced cell apoptosis in A431 cells. Most notably, upregulation of TSLC1 expression reduced the numbers of colony formation and tumorigenicity. Collectively, our results presented herein suggest that TSLC1 as tumor suppressor may play prominent roles in development and progression of CSCC via regulation of different biological processes.

Tumor suppressor in lung cancer-1 (TSLC1) mediated by dual-regulated oncolytic adenovirus exerts specific antitumor actions in a mouse model

The tumor suppressor in lung cancer-1 (TSLC1) is a candidate tumor suppressor of lung cancer, and frequently inactivated in primary non-small cell lung cancer (NSCLC). In this study, we investigated the effects of TSLC1 mediated by a dual-regulated oncolytic adenovirus on lung cancer, and the mechanisms underlying the antitumor actions. The recombinant virus Ad·sp-E1A(Δ24)-TSLC1 was constructed by inserting the TSLC1 gene into the dual-regulated Ad·sp-E1A(Δ24) vector, which contained the survivin promoter and a 24 bp deletion within E1A. The antitumor effects of Ad·sp-E1A(Δ24)-TSLC1 were evaluated in NCI-H460, A549, and H1299 lung cancer cell lines and the normal fibroblast cell line MRC-5, as well as in A549 xenograft model in nude mice. Cell viability was assessed using MTT assay. The expression of TSLC1 and activation of the caspase signaling pathway were detected by Western blot analyses. The tumor tissues from the xenograft models were examined using H&E staining, IHC, TUNEL, and TEM analyses. Infection of A549 lung cancer cells with Ad·sp-E1A(Δ24)-TSLC1 induced high level expression of TSLC1. Furthermore, the Ad·sp-E1A(Δ24)-TSLC1 virus dose-dependently suppressed the viability of NCI-H460, A549, and H1299 lung cancer cells, and did not affect MRC-5 normal fibroblast cells. Infection of NCI-H460, A549, and H1299 lung cancer cells with Ad·sp-E1A(Δ24)-TSLC1 induced apoptosis, and increased activation of caspase-8, caspase-3 and PARP. In A549 xenograft model in nude mice, intratumoral injection of Ad·sp-E1A(Δ24)-TSLC1 significantly suppressed the tumor volume, and increased the survival rate (from less than 15% to 87.5% at d 60). Histological studies showed that injection of Ad·sp-E1A(Δ24)-TSLC1 caused tumor cell apoptosis and virus particle propagation in tumor tissues. The oncolytic adenovirus Ad·sp-E1A(Δ24)-TSLC1 exhibits specific antitumor effects, and is a promising agent for the treatment of lung cancer.

Tumor suppressor in lung cancer 1 and CD105 expression in esophageal carcinoma

Objective To investigate the expression of tumor suppressor in lung cancer 1 (TSLC1) and microvessel density (MVD) marked with CD105 in esophageal carcinoma.Methods Envision immunohistochemical method was used to assess the expression of TSLC1 and MVD marked with CD105 in 45 cases of esophageal carcinoma tissues and non-cancerous adjacent esophageal tissues.Results The expression rate of TSLC1 was 42.22％ (19/45) in esophageal carcinoma tissues,and 91.11％ (41/45) in non-cancerous adjacent esophageal tissues (P ＜ 0.01).The expression of MVD marked with CD105 was 38.25 ± 4.37 in esophageal carcinoma tissues,and 11.39 ± 1.52 in non-cancerous adjacent esophageal tissues (P ＜ 0.01).The expression of TSLC1 was correlated to TNM stage and lymph node metastasis (P ＜ 0.05).There was a close correlation between the expression of MVD marked with CD105 and histologic grade,TNM stage and lymph node metastasis (P ＜ 0.05).Conclusion TSLC1 and CD105 may play a significant role in the onset and progression of esophageal carcinoma. Key words: Esophageal carcinoma; Tumor suppressor in lung cancer 1; CD105

TSLC1 expression discriminates cutaneous melanomas from dysplastic nevi

Cutaneous melanoma is a malignant tumor of melanocytes that causes the majority of skin cancer-related deaths. However, sometimes, discrimination between dysplastic nevi and early melanomas is difficult, even for experienced pathologists. Besides histology, the silencing of tumor suppressor genes aids in the diagnosis of melanoma. We have shown previously that tumor suppressor in lung cancer 1 (TSLC1) is a tumor suppressor gene, and its silencing through aberrant promoter methylation is associated with the generation of cutaneous melanoma. To examine TSLC1 expression in melanocytic skin lesions to determine whether it can serve as a diagnostic marker in histologically questionable lesions. Cytoplasmic localization of the expression of the TSLC1 gene was detected by immunohistochemistry; the levels of TSLC1 mRNA and protein were detected by quantitative real-time reverse transcription-PCR and western blot, respectively. Using immunohistochemistry, the average TSLC1 expression levels in cutaneous melanomas decreased approximately 3.6-fold (n=20) as compared with dysplastic nevi (n=30) and 3.7-fold as compared with normal skin (n=25). The average expression levels of TSLC1 mRNA and protein in dysplastic nevi lesions and normal skin were significantly higher than the levels in cutaneous melanomas. No significant changes in TSLC1 mRNA and protein expressions were found between normal skin and dysplastic nevi. Our results show that a loss of TSLC1 frequently occurs in cutaneous melanoma, and indicate that it could serve as a diagnostic marker for cutaneous melanoma in histologically questionable lesions.

Down-regulation of tumor suppressor in lung cancer 1 (TSLC1) expression correlates with poor prognosis in patients with colon cancer

Tumor suppressor in lung cancer 1 (TSLC1), a novel tumor suppressor gene, has been reported to be frequently inactivated in a variety of human malignant tumors. The aim of this study was to detect TSLC1 expression in human colon cancer and to analyze its association with prognosis of patients with colon cancer. Using quantitative real-time PCR and Western blot analysis, we found significantly decreased expression of TSLC1 in primary colon tumor tissues (n = 30) compared with adjacent normal tissues. Immunohistochemistry analysis also found decreased TSLC1 expression in 41.3 % (33/80) colon tumor tissues. In clinicopathological analysis, loss of TSLC1 expression significantly correlated with female gender and lymph node metastasis of colon cancer patients (P < 0.05). In addition, decreased expression of TSLC1 in tumors was found to be closely associated with a poor prognosis (P = 0.037, log-rank test), and multivariate analysis showed that lower TSLC1 protein expression was an independent prognostic factor for colon cancer patients. Our study suggests that down-regulated expression of TSLC1 may play an important role in the progression of colon cancer and TSLC1 expression may serve as a useful marker for the prognostic evaluation of patients with colon cancer.

Tumor suppressor TSLC1 is implicated in cell proliferation, invasion and apoptosis in laryngeal squamous cell carcinoma by regulating Akt signaling pathway

Overwhelming evidence has demonstrated that TSLC1 (tumor suppressor in lung cancer 1), a novel tumor suppressor, is crucially implicated in various biological processes including progression, proliferation and apoptosis during tumorigenesis. However, the exact functions and molecular details of TSLC1 in laryngeal cancer remain ill-defined. Here, the expression of TSLC1 in laryngeal squamous cell carcinoma (LSCC) tissues and cells was detected, and the biological roles of TSLC1 in LSCC cells were investigated. The results showed that expressions of TSLC1 mRNA and protein were significantly reduced in LSCC tissues with low expression in 18 of 85 (21.18 %) and 16 of 85 (18.82 %), respectively. Additionally, statistical analysis revealed a significant correlation of TSLC1 expression with TNM staging and lymph node metastases (P < 0.05), but not related to age, gender and tumor differentiation (P > 0.05). Elevation of TSLC1 level inhibited cell proliferation, reduced cell invasion in vitro and induced cell apoptosis in Hep-2 cells, most importantly, TSLC1 upregulation decreased the level of pAkt, but not changed the level of total Akt in Hep-2 cells. Stepwise investigations demonstrated that overexpression of TSLC1 in Hep-2 cells increased caspase-3 activity and expressions of bax and p21 proteins but decreased the levels of bcl-2, MMP-2 and MMP-9 proteins. These data suggest that TSLC1 may exert essential roles in the progression and development of LSCC, and thus TSLC1 may be a potential molecular target for LSCC treatment.

Trichosanthin inhibits DNA methyltransferase and restores methylation-silenced gene expression in human cervical cancer cells

Epigenetic silencing of tumor suppressor genes is a well-established oncogenic process and the reactivation of tumor suppressor genes that have been silenced by promoter methylation is an attractive molecular target for cancer therapy. In this study, we investigated the demethylation activity of trichosanthin (TCS, the main bioactive component isolated from a Chinese medicinal herb) and its possible mechanism of action in cervical cancer cell lines. HeLa human cervical adenocarcinoma and CaSki human cervical squamous carcinoma cells were treated with various concentrations (0, 20, 40 and 80 µg/ml) of TCS for 48 h and the mRNA and protein expression levels of the tumor suppressor genes adenomatous polyposis coli (APC) and tumor suppressor in lung cancer 1 (TSLC1) were detected using reverse transcription (RT)-PCR and western blotting, respectively. We analyzed the methylation status of APC and TSLC1 using methylation-specific PCR (MSP). The expression levels and enzyme activity of DNA methyltransferase 1 (DNMT1) were also examined. The mRNA and protein expression levels of APC and TSLC1 were increased following treatment with various concentrations (0, 20, 40 and 80 µg/ml) of TCS for 48 h. The expression of the APC gene increased 2.55±0.29-, 3.44±0.31- and 4.36±0.14-fold, respectively. The expression of the TSLC1 gene increased 2.28±0.15-, 4.23±0.88- and 6.09±0.23-fold, respectively. MSP detection showed that TCS induced demethylation in HeLa and CaSki cells and that this demethylation activity was accompanied by the decreased expression of DNMT1 and reduced DNMT1 enzyme activity. Our experimental results demonstrate for the first time that TCS is capable of restoring the expression of methylation-silenced tumor suppressor genes and is potentially useful as a demethylation agent for the clinical treatment of human cervical cancer.

Effect of TSLC1 gene on growth and apoptosis in human esophageal carcinoma Eca109 cells

IntroductionTo explore the effect of tumor suppressor in lung cancer 1 (TSLC1) on proliferation and apoptosis in esophageal cancer Eca109 cells.Material and methodsEca109 cells were divided into three groups: TSLC1 transfected group (TTG), mock group (MG) and untransfected group (UTG). The TTG and MG were transfected transiently with the pIRES2-EGFP-TSLC1 eukaryotic expression vector and pIRES2-EGFP vector respectively. The UTG was a blank control. The TSLC1 expression in TTG was analyzed with the fluorogram and RT-PCR method. Cell proliferation was measured with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium (MTT) assay. Cell cycle was measured by flow cytometry (FCM). Cell apoptosis was detected by Annexin-V/PI double staining FCM.ResultsGreen color was found in TTG and MG. The band of TSLC1 mRNA of TTG was located at about 1400 bp by RT-PCR and agarose gel electrophoresis assay. The TSLC1 inhibited cell proliferation significantly in MTT assay, and the cell proliferation was slower in TTG than MG and UTG. After TSLC1 transfection, cell numbers increased in G0/G1 phase and decreased in S phase. Forty-eight hours after transfection, the apoptosis rate and death rate of TTG were higher than MG and UTG. Thus TSLC1 induced Eca109 cells to apoptosis.ConclusionsThe TSLC1 gene had a potent effect on cell proliferation inhibition, G1/S cell cycle arrest and induction of cell apoptosis in Eca109 cells.

Effects of tumor suppressor in lung cancer-1 overexpression on gene expressions involved in glucose and lipid metabolism in liver cells

The effects of tumor suppressor in lung cancer-1(TSLC1)upregulation on gene expressions involved in glucose and lipid metabolism in Hepa1-6 cells were investigated.The results showed that TSLC1 overexpression decreased fatty acid synthase and acetyl CoA carboxylase expressions(P<0.05 or P<0.01),increased adipose triglyceride lipase expression(P<0.05),and did not change hormone-sensitive lipase,glucose transporter (GLUT)1,and GLUT4 expressions.These results suggest that TSLC1 overexpression may promote lipolysis and inhibit adipogenesis in liver cells. Key words: Tumor suppressor in lung cancer-1; Hepal-6 cells; Glucose-lipid metabolism; Gene expression

Trichosanthin enhances anti-tumor immune response in a murine Lewis lung cancer model by boosting the interaction between TSLC1 and CRTAM

Trichosanthin (TCS), extracted from the Chinese medicinal herb Trichosanthes kirilowi, has shown promise for the inhibition of tumor growth. However, its immunomodulatory effect on tumor-host interaction remains unknown. In this study, we focused on the effect of TCS on murine anti-tumor immune response in the 3LL Lewis lung carcinoma tumor model and explored the possible molecular pathways involved. In addition to inhibiting cell proliferation and inducing apoptosis in the 3LL tumor, TCS retarded tumor growth and prolonged mouse survival more significantly in C57BL/6 immunocompetent mice than in nude mice. This reflected the fact that the host immune system was involved in tumor eradication. Using FACS analysis, we found that TCS increased the percentage of effector T cells, particularly Interferon-gamma (IFN-γ) producing CD4(+) and CD8(+) T cells from tumor-bearing mice. TCS also promoted the vigorous proliferation of antigen-specific effector T cells, markedly increased Th1 cytokine secretion and elicited more memory T cells in tumor-bearing mice, consequently enhancing the anti-tumor response and inducing immune protection. Furthermore, we found that TCS upregulated the expression of tumor suppressor in lung cancer 1 (TSLC1) in 3LL tumor cells and the expression of its ligand, class I-restricted T cell-associated molecule (CRTAM), in effector T cells. Blocking TSLC1 expression with small interfering RNA (siRNA) significantly eliminated the effects of TCS on the proliferation and cytokine secretion of effector T cells, suggesting that TCS enhances anti-tumor immune response at least partially by boosting the interaction between TSLC1 and CRTAM. Collectively, our data demonstrate that TCS not only affects tumor cells directly, but also enhances anti-tumor immunity via the interaction between TSLC1 and CRTAM. These findings may lead to the development of a novel approach for tumor regression.

Loss/Down-Regulation of Tumor Suppressor in Lung Cancer 1 Expression Is Associated With Tumor Progression and Is a Biomarker of Poor Prognosis in Ovarian Carcinoma

The tumor suppressor in lung cancer 1 (TSLC1) has been identified as a putative tumor suppressor gene in non-small cell lung cancer. Although loss of TSLC1 has been observed in a number of human malignancies, the expression levels of TSLC1 gene in ovarian cancer and its clinical or prognostic significance have not been investigated. Protein expression levels of TSLC1 was explored by semiquantitative immunohistochemical staining on archival formalin-fixed, paraffin-embedded pathological specimen consisting of 30 normal ovaries, 30 ovarian cystadenomas, 40 borderline ovarian tumors, and 160 invasive ovarian carcinomas. The TSLC1 immunohistochemical staining results were then correlated with various clinicopathologic parameters and patient prognosis using various statistical models. Significantly decreased, or complete loss of, protein expression of the TSLC1 gene was observed in 59% ovarian carcinomas, 45% borderline tumors, and 7% cystadenomas, but in none of the normal ovaries (0%). In ovarian carcinomas, decreased TSLC1 expression was significantly correlated with lymph node metastasis (pN, P = 0.001), distant metastasis (pM, P = 0.028), and more advanced International Federation of Gynecology and Obstetrics stages (P = 0.008). By univariate survival analysis on the ovarian carcinoma cohorts, decreased TSLC1 protein expression was significantly associated with shortened patient survival (mean: 26.9 months in tumors with complete loss of TSLC1 vs 63.1 months in tumors with significantly decreased TSLC1 vs 94.3 months in tumors with normal levels of TSLC1; P < 0.001). By multivariate analysis, TSLC1 protein expression remained as a significant and independent prognostic factor for the prediction of patient survival (P = 0.003). Decreased protein expression of the TSLC1 gene might be important in conferring a more aggressive behavior in ovarian carcinoma. Thus, TSLC1 may be used as an independent prognostic molecular marker for patients with ovarian carcinoma.