Chenxi Zhong

LDHA is necessary for the tumorigenicity of esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most common lethal tumors in the world, and the development of new therapeutic targets is needed. Recent studies have shown that aerobic glycolysis, also known as the Warburg effect, mediated the anti-apoptotic effects in cancer cells. Lactate dehydrogenase A (LDHA) which executed the final step of aerobic lactate production has been reported to be involved in the tumor progression. However, the function of LDHA in ESCC has not been investigated. In this study, it was found that LDHA was up-regulated in ESCC clinical samples. Knockdown of the expression of LDHA inhibited cell growth and cell migration in vitro as well as tumorigenesis in vivo. With regard to the molecular mechanism, silencing the expression of LDHA was related to decreased AKT activation and cyclin D1 expression and increased cleavage of PARP and caspase 8. Taken together, our findings suggest that LDHA plays an important role in the progression of ESCC by modulating cell growth, and LDHA might be a potential therapeutic target in ESCC.

Clinical Outcomes of Thoracoscopic Lobectomy for Patients With Clinical N0 and Pathologic N2 Non-Small Cell Lung Cancer

BACKGROUND We compared the surgical outcomes in patients with clinical N0 and pathologic N2 (cN0-pN2) non-small cell lung cancer (NSCLC) who underwent video-assisted thoracoscopic surgery (VATS) lobectomy and open thoracotomy to evaluate the role of VATS lobectomy for cN0-pN2 disease. METHODS Between March 2006 and August 2011, 1,456 patients with clinical N0 NSCLC disease underwent lobectomy with systematic node dissection (SND) at Shanghai Chest Hospital. Of those patients, 157 were shown to have cN0-pN2 NSCLC. Of those, 67 patients underwent VATS lobectomy, and 90 patients underwent open lobectomy. SND was performed in all 157 patients. Clinicopathologic factors, local recurrence rates, and survival rates were compared. RESULTS The two groups were similar in age, sex, and pulmonary function. The VATS approach was associated with significantly shorter chest tube duration and postoperative stay than was the thoracotomy approach. Operative mortality, morbidity, and recurrence did not differ between the two groups. There was no significant difference between the two types of operation in numbers of total lymph nodes removed (17.4 ± 6.1 in the VATS group vs 18.1 ± 7.2 in the open group, p = 0.78) and mediastinal lymph nodes removed (11.7 ± 5.6 in the VATS group vs 12.0 ± 5.1 in the open group, p = 0.84). Similarly, the two groups were not significantly different with regard to stations of total lymph nodes removed (7.6 ± 1.9 in the VATS group vs 7.8 ± 2.3 in the open group, p = 0.81) and mediastinal lymph nodes removed (4.5 ± 1.1 in the VATS group vs 4.7 ± 1.3 in the open group, p = 0.71). The rates of overall survival and disease-free 5-year survival were not significantly different between the two groups. CONCLUSIONS The clinical outcomes of thoracoscopic lobectomy were comparable to those of thoracotomy for patients with cN0-pN2 NSCLC. Single-station N2 is a good prognostic factor for disease-free survival in these patients.

Down-regulation of LATS2 in non-small cell lung cancer promoted the growth and motility of cancer cells

LATS2 (Large tumor suppressor) has been reported to be dys-regulated in several cancer types. However, its function in non-small cell lung cancer (NSCLC) remains poorly understood. Here, it was found that the expression level of LATS2 was decreased in NSCLC tissues. Moreover, forced expression of LATS2 in NSCLC cells inhibited cell growth and migration, while knockdown of the expression of LATS2 promoted the tumorigenicity of NSCLC cells. Mechanistically, LATS2 was found to negatively regulate NF-κB signaling in NSCLC cells. Taken together, our study suggested that down-regulation of LATS2 was very important in the progression of NSCLC, and restoring the function of LATS2 might be a promising therapeutic strategy for NSCLC.

Hydrogen saline is protective for acute lung ischaemia/reperfusion injuries in rats

BACKGROUND Protective effects of saturated hydrogen (H(2)) saline on cardiac ischaemia-reperfusion (I/R) injury have been demonstrated previously. This study was designed to show that hydrogen-rich saline is protective in preventing lung I/R injury in rats. METHODS Adult male Sprague-Dawley rats underwent 45 min occlusion of the right lung roots and 120 min reperfusion. Rats were divided randomly into three groups: sham-operated control group, I/R plus saline treatment, and I/R plus hydrogen-rich saline treatment (0.6 mmol/L, 0.5 ml/kg/d). Three days of intraperitoneal injection of hydrogen-rich saline before the reperfusion combined with immediate administration of hydrogen-rich saline after the reperfusion were performed. Following reperfusion, the lung tissue and the pulmonary artery was immediately obtained and the W/D ratio, pulmonary artery contraction and relaxation ability, H-E staining, TUNEL staining, caspase-3, MDA, 8-OHdG content and measurement of such biomarkers as WBC, CRP were measured or carried out. RESULTS Hydrogen saline significantly protected vasoactivity of the pulmonary artery, reduced pulmonary oedema, decreased lung malondialdehyde (MDA), 8-OHdG concentration, alleviated lung epithelial cell apoptosis and lowered the level of such biomarkers as WBC, CRP, ALT and TBiL. CONCLUSIONS It is concluded that hydrogen-rich saline is a novel, simple, safe and effective method to attenuate pulmonary I/R injury.

HMGCR is necessary for the tumorigenecity of esophageal squamous cell carcinoma and is regulated by Myc

Hydroxymethylglutaryl coenzyme A reductase (HMGCR), the rate-limiting enzyme of mevalonate pathway, has been involved in the tumorigenesis of several tumor types. Our previous study has showed that statin, the inhibitor of HMGCR, inhibited the tumorigenecity of esophageal squamous cell carcinoma (ESCC) in vitro and in vivo. However, the function of HMGCR in the carcinogenesis of ESCC cells remains unknown. In this study, we have observed the up-regulation of HMGCR in ESCC tissues compared with the paired normal tissues. Over-expression of HMGCR in ESCC cells promoted cell growth and migration, while knockdown of the expression of HMGCR inhibited the growth, migration and colony formation of ESCC cells in vitro and in vivo. Furthermore, we found that oncogene Myc positively regulated the expression of HMGCR. Taken together, our study revealed the pivotal function of HMGCR and mevalonate pathway in the progression of ESCC and supported the clinical application of statin.

Mevalonate pathway is a therapeutic target in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most common lethal tumors in the world. Thus, it is very urgent to develop new therapeutic targets against this disease. The mevalonate (MVA) pathway, paced by its rate-limiting enzyme, hydroxymethylglutaryl coenzyme A reductase, is required for the generation of several fundamental end products including cholesterol and isoprenoids. The function of the MVA pathway in ESCC has not been investigated. In this study, it was found that the MVA pathway was upregulated in ESCC clinical samples. Statin, the inhibitor of the MVA pathway, exerted potent cytotoxicity against human ESCC cells by inhibiting cell growth and proliferation, while it exerted lesser effects on non-tumorigenic SHEE cells. Further study revealed that statin could potently induce cell apoptosis and cell cycle arrest and also dose-dependently inhibit the growth of xenograft tumors in nude mice. With regard to the molecular mechanism, statin treatment was related to decreased extracellular signal-regulated kinase activation and proliferating cell nuclear antigen, cyclin D1 expression, and increased cleavage of poly(ADP-ribose) polymerase. Taken together, our findings suggest that the MVA pathway plays an important role in the progression of ESCC by modulating cell growth and statin might be a potential therapeutic agent in ESCC.

TRAF6 promoted the metastasis of esophageal squamous cell carcinoma

Esophageal cancer is one of the most aggressive malignancies and has been ranked as the sixth leading cause of cancer-related death in the world. It is very urgent to find new therapeutic targets. Although tumor necrosis factor receptor-associated factor 6 (TRAF6) was initially identified as an adaptor for NF-κB signaling, recently it has been found to be involved in cancer by modulating various signaling pathways. In the previous study, we have found that TRAF6 promoted the growth of esophageal squamous cell carcinoma (ESCC) cell in vitro and in vivo. However, the effects of TRAF6 on the migration and metastasis of ESCC cells are poorly understood. Here, we found that TRAF6 promoted migration and metastasis of ESCC cells through modulating Ras signaling. Overexpression of TRAF6 promoted the migration of ESCC cells and immortalized esophageal epithelial cells, while knock down the expression of TRAF6 inhibited the migration and metastasis of ESCC cells in vitro and in vivo. Mechanically, TRAF6 binds Ras with its N-terminal and activated Ras signaling. Taken together, TRAF6 played an important role in the metastasis of ESCC and might be a promising therapeutic target.

Downregulation of MED23 promoted the tumorigenecity of esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is one of the most common tumors in the world. It is very urgent to develop new therapeutic strategies. MED23, a component of the mediator complex, is known as a hub to integrate various signaling pathways. However, the function of MED23 in ESCC remains unknown. Here, we found that the expression of MED23 was downregulated in the clinical ESCC samples and the expression of MED23 reversely correlated with tumor size and clinical stage. Moreover, overexpression of MED23 in ESCC cells inhibited cell growth dramatically, while downregulation of MED23 promoted the tumorigenecity of ESCC cells in vitro and in vivo. Mechanistically, knockdown the expression of MED23 inhibited cell apoptosis by downregulation of Bax, activated Caspase 3, activated Caspase 9 and upregulation of cyclinD1 and Bcl2. Taken together, our study revealed the suppressive role of MED23 in ESCC and MED23 might be an important therapeutic target in ESCC.

LATS2 inhibits the activity of NF-κ B signaling by disrupting the interaction between TAK1 and IKKβ

NF-κB signaling plays very important role in the tumorigenesis of nonsmall cell lung cancer (NSCLC). However, the molecular mechanisms for the dysregulation of NF-κB signaling in NSCLC have not been fully understood. In the previous reports, we have showed that large tumor suppressor gene 2 (LATS2) inhibited NF-κB signaling in NSCLC cells, whereas the details for the mechanism remain unknown. Here, we reported that LATS2 is a suppressor of tumor necrosis factor (TNF-α)-induced NF-κB signaling by inhibiting the interaction between TAK1 and IKKβ. Overexpression of LATS2 largely blocked TNF-α-induced NF-κB activation and IκBα degradation, whereas knockdown of LATS2 showed the opposing results. Mechanistically, we identified that LATS2 interacted with IKKβ and blocked the interaction between IKKβ and TAK1. Our results indicate that LATS2 functions as a pivotal negative regulator in TNF-α-induced activation of NF-κB via disrupting the interaction of TAK1 with IKKβ.

Upregulation of mediator MED23 in non-small-cell lung cancer promotes the growth, migration, and metastasis of cancer cells.

Mediator complex subunit MED23 has been reported to facilitate the transformation induced by oncogenic Ras in non-small-cell lung carcinoma (NSCLC). However, the expression pattern and biological functions of MED23 in the progression of NSCLC are not fully understood. In this study, it was found that the expression of MED23 was significantly upregulated in NSCLC samples compared to their adjacent normal tissues. Moreover, in the biological function studies, overexpression of MED23 was further validated to promote the growth, migration, and metastasis of NSCLC cells, while knockdown of the expression of MED23 inhibited the growth, migration, and metastasis of NSCLC cells in vitro and in vivo. Mechanistically, MED23 was found to interact with beta-catenin and activate beta-catenin/TCF signaling. Our study demonstrated that MED23 played an oncogenic role in the progression of NSCLC and that MED23 might be a promising target for the treatment of NSCLC.