Lichun Sun

Angiotensin II type 1 receptor antagonists inhibit cell proliferation and angiogenesis in breast cancer.

Angiotensin II type 1 receptor (AT1R) promotes tumor invasion, migration, metastasis and angiogenesis. We explored the potential antitumor effects of AT1R antagonists in breast cancer. We found that angiotensin II promoted cell proliferation and upregulated the expression of vascular endothelial growth factor A (VEGF-A) in MCF-7 cells. Losartan downregulated the expression of VEGF-A in MCF-7 cells treated with angiotensin II. Candesartan downregulated the expression of VEGF-A in mice bearing MCF-7 xenografts and inhibited tumor growth and angiogenesis. AT1R and VEGF-A expression correlated with increased microvascular density in 102 breast cancer patients. Our data suggest that AT1R antagonists might be useful to suppress breast cancer by inhibiting the angiotensin II.

ABCC3 as a marker for multidrug resistance in non-small cell lung cancer

Multidrug resistance (MDR) contributes to the failure of chemotherapy and high mortality in non-small cell lung cancer (NSCLC). We aim to identify MDR genes that predict tumor response to chemotherapy. 199 NSCLC fresh tissue samples were tested for chemosensitivity by MTT assay. cDNA microarray was done with 5 samples with highest resistance and 6 samples with highest sensitivity. Expression of ABCC3 mRNA and protein was detected by real-time PCR and immunohistochemisty, respectively. The association between gene expression and overall survival (OS) was examined using Cox proportional hazard regression. 44 genes were upregulated and 168 downregulated in the chemotherapy-resistant group. ABCC3 was one of the most up-regulated genes in the resistant group. ABCC3-positive expression correlated with lymph node involvement, advanced TNM stage, more malignant histological type, multiple-resistance to anti-cancer drugs, and reduced OS. ABCC3 expression may serve as a marker for MDR and predictor for poor clinical outcome of NSCLC.

Carbamazepine promotes Her-2 protein degradation in breast cancer cells by modulating HDAC6 activity and acetylation of Hsp90

Histone deacetylase 6 (HDAC6) inhibition, recently, has been shown to promote the acetylation of heat-shock protein 90 (Hsp90) and disrupt its chaperone function. Her-2 oncoprotein is identified as a client protein of Hsp90. Therefore, in this study we examined the effect of carbamazepine, which could inhibit HDAC on Hsp90 acetylation and Her-2 stability. The results of this study demonstrate that while carbamazepine had no effect on the Her-2 mRNA level, it induced Her-2 protein degradation via the proteasome pathway by disrupting the chaperone function of Hsp90 in SK-BR-3 cells. Mechanistically, carbamazepine could enhance the acetylation of α-tubulin, indicating its inhibitory effect on HDAC6. Functionally, carbamazepine could synergize with trastuzumab or geldanamycin to promote Her-2 degradation and inhibit breast cancer cell proliferation. Thus, this study has potential clinical implications by providing a promising strategy to overcome the development of resistance against trastuzumab therapy for breast cancer.

miRNA-378 reverses chemoresistance to cisplatin in lung adenocarcinoma cells by targeting secreted clusterin

Cisplatin resistance is a major obstacle in the treatment of NSCLC, and its mechanism has not been fully elucidated. The objectives of the study were to determine the role of miR-378 in the sensitivity of lung adenocarcinoma cells to cisplatin (cDDP) and its working mechanism. With TargetScan and luciferase assay, miR-378 was found to directly target sCLU. miR-378 and sCLU were regulated in A549/cDDP and Anip973/cDDP cells to investigate the effect of miR-378 on the sensitivity and apoptotic effects of cDDP. The effect of miR-378 upregulation on tumor growth was analyzed in a nude mouse xenograft model. The correlation between miR-378 and chemoresistance was tested in patient samples. We found that upregulation of miR-378 in A549/cDDP and Anip973/cDDP cells significantly down-regulated sCLU expression, and sensitized these cells to cDDP. miR-378 overexpression inhibited tumor growth and sCLU expression in a xenograft animal model. Analysis of human lung adenocarcinoma tissues revealed that the cDDP sensitive group expressed higher levels of miR-378 and lower levels of sCLU. miR-378 and sCLU were negatively correlated. To conclude, we identified sCLU as a novel miR-378 target, and we showed that targeting sCLU via miR-378 may help disable the chemoresistance against cisplatin in lung adenocarcinoma cells.

Baseline staging tests based on molecular subtype is necessary for newly diagnosed breast cancer

BackgroundBone scanning (BS), liver ultrasonography (LUS), and chest radiography (CXR) are commonly recommended for baseline staging in patients with newly diagnosed breast cancer. The purpose of this study is to demonstrate whether these tests are indicated for specific patient subpopulation based on clinical staging and molecular subtype.MethodsA retrospective study on 5406 patients with newly diagnosed breast cancer was conducted to identify differences in occurrence of metastasis based on clinical staging and molecular subtypes. All patients had been evaluated by BS, LUS and CXR at diagnosis.ResultsComplete information on clinical staging was available in 5184 patients. For stage I, II, and III, bone metastasis rate was 0%, 0.6% and 2.7%, respectively (P < 0.01); liver metastasis rate was 0%, 0.1%, and 1.0%, respectively (P < 0.01); lung metastasis rate was 0.1%, 0.1%, and 0.7%, respectively (P < 0.01). Complete information on molecular subtype was available in 3411 patients. For Luminal A, Luminal B (HER2-), Luminal BH (HER2+), HER2+ overexpression, and Basal-like, bone metastasis rate was 1.4%, 0.7%, 2.5%, 2.7%, and 0.9%, respectively (P < 0.05); liver metastasis rate was 0.1%, 0.1%, 1.0%, 1.1%, and 0.9%, respectively (P < 0.01); lung metastasis rate was 0.20%, 0%, 0%, 0.27%, and 0.9%, respectively (P < 0.05). cT (tumor size), cN (lymph node), PR (progesterone receptor), and HER2 status predicted bone metastasis (P < 0.05). cT, cN, ER (estrogen receptor), PR, and HER2 status predicted liver metastasis (P < 0.05). cT, cN, and PR status predicted lung metastasis (P < 0.05).ConclusionThese data indicate that based on clinical staging and molecular subtypes, BS, LUS and CXR are necessary for patients with newly diagnosed breast cancer.

Luminal (Her2 negative) prognostic index and survival of breast cancer patients

PURPOSE The group of luminal (Her2 negative) is distinguished from other subtypes of breast cancer. We aimed to produce a prognostic index specific for luminal (Her2 negative) subtype breast cancer that could assist clinical treatment. METHODS The test set comprised 406 consecutive luminal (Her2 negative) breast cancer patients. The relationship of 11 clinicopathologic factors including survivin with the 5-year disease-free survival was analyzed. RESULTS In univariate analysis, TNM stage, surgery, tumor size, lymph node involvement, and survivin expression were prognostic factors. In multivariate analysis, tumor size [HR (95% CI): 1.98 (1.12-3.49), p=0.019], the number of lymph node metastasis [HR (95% CI): 1.75 (1.33-2.29), p<0.0001] and the expression of progesterone receptor [HR (95% CI): 0.58 (0.36-0.95), p=0.029] can independently predict prognosis. Prognostic index (PI) was calculated as 0.68×tumor size+0.56×the number of lymph node metastasis-0.54×PR. According to the PI, patients were categorized into three groups: low, middle, and high risk group with the 5-year disease-free survival rates of 91.91%, 84.97% and 70.47%, respectively (P<0.001). In the validation set, the luminal prognostic index (LPI) remained significant. CONCLUSION The LPI may be a useful tool for evaluating the outcome of patients with luminal (Her-2 negative) breast cancer.

Mammalian Eps15 homology domain 1 promotes metastasis in non-small cell lung cancer by inducing epithelial-mesenchymal transition

The identification of the earliest molecular events responsible for the metastatic dissemination of non-small cell lung cancer (NSCLC) remains critical for early detection, prevention, and treatment interventions. In this study, we hypothesized that Mammalian Eps15 homology domain 1 (EHD1) might be responsible for the metastatic behavior of cells in NSCLC. We demonstrated that upregulation of EHD1 is associated with lymph nodes metastasis and unfavorable survival in patients with NSCLC. EHD1 knockdown inhibited the invasion and migration of human NSCLC cells, and overexpression of EHD1 increased the metastatic potential of lung cancer cells. Using the Affymetrix Human Gene 1.0 ST platform, microarray analysis revealed that an association between EHD1 and epithelial-mesenchymal transition (EMT), supported by downregulation of mesenchymal markers and upregulation of epithelial markers following knockdown of EHD1 in cell lines. Moreover, overexpression of EHD1 induced the EMT and increased the metastatic potential of lung cancer cells in vitro and in vivo. These results provide a model to illustrate the relationship between EHD1 expression and lung cancer metastasis, opening up new avenues for the prognosis and therapy of lung cancer.

Expression of calcium sensing receptor and E-cadherin correlated with survival of lung adenocarcinoma.

It has been reported that the calcium sensing receptor (CaSR), a widely expressed G protein‐coupled receptor, can stimulate cell differentiation and proliferation. However, in malignant tumors, loss of CaSR expression has been associated with tumorigenesis, metastasis, and progression. Recent studies have indicated that the CaSR could promote the expression of E‐cadherin, which was considered a tumor suppressor. However, in human lung adenocarcinoma, the importance of the CaSR and E‐cadherin has not been sufficiently investigated.

Increased Expression of Eps15 Homology Domain 1 is Associated with Poor Prognosis in Resected Small Cell Lung Cancer.

One of the great challenges of small cell lung cancer (SCLC) treatment is identifying patients at high risk for recurrence after surgical resection and chemotherapy. We examined Eps15 homology domain 1 (EHD1) protein expression in paraffin sections of 85 resected SCLC tissues, metastatic lymph nodes and normal bronchial epithelial tissues using immunohistochemistry to study the correlation between EHD1 expression and patient clinicopathological features. Within these variables, disease free survival (DFS) analyzed by the log-rank test was constructed using the multivariate Cox proportional hazards regression model and Kaplan-Meier analysis. Immunohistochemistry results showed that EHD1 protein was significantly increased in SCLC tissues compared with normal tissues (P < 0.001). Moreover, EHD1 expression was positively correlated with tumor size (P = 0.019). Multivariate Cox proportional hazards model analysis showed that EHD1 expression (P = 0.047; HR, 1.869; 95% CI, 1.008-3.466) and American Joint Committee on Cancer (AJCC) status (P < 0.001; HR, 1.412; 95% CI, 1.165-1.711) were independent prognostic indicators of DFS. In conclusion, these data demonstrated a remarkable correlation between the cytoplasmic expression of EHD1 protein and adverse prognosis in patients receiving early-stage cisplatin treatment for resected SCLC.