Xuesong Chen

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.

Angiotensin II/angiotensin II type I receptor (AT1R) signaling promotes MCF-7 breast cancer cells survival via PI3-kinase/Akt pathway.

Angiotensin II (Ang II) is a bioactive peptide of the renin–angiotensin system, acting not only as a vasoconstrictor but also as a growth promoter via angiotensin II type 1 receptor (AT1R) in some cancer. In this study, we examined the mechanisms by which Ang II affected the cell proliferation in AT1R‐positive MCF‐7 human breast cancer cells. Ang II stimulated the growth of breast cancer cells in a dose‐ and time‐dependent manner. The maximal proliferation effect on MCF‐7 cells was obtained with 10−4 M Ang II at 24 h. Losartan (10−5 M, an AT1R antagonist) significantly decreased the level of Ang‐II‐induced proliferative effects, whereas PD123319 (10−5 M, an AT2R antagonist) had no effects. Moreover, Ang II could significantly accelerate S‐phase progression, which was inhibited by losartan (10−5 M) or LY294002 (50 µM, a PI3‐kinase inhibitor). In addition, Ang II caused rapid activation of p‐Akt in a dose‐ and time‐dependent manner. 10−4 M Ang II induced a significant increase of p‐Akt in 15 min. The peak level of p‐Akt could be persisted for at least 6 h. Among the signaling molecules downstream of Akt, we revealed that Ang II also significantly upregulated CyclinD1, GSK3β, and downregulated p27. Pretreatment with losartan (10−5 M) or LY294002 (50 µM) could significantly suppress these effects of Ang II. These findings suggest that Ang II plays a role in the growth of AT1R‐positive breast cancer cells through PI3‐kinase/Akt pathway activation. Therefore, targeting Ang II/AT1R signaling could be a novel therapeutic for breast cancer. J. Cell. Physiol. 225: 168–173, 2010.

Knockdown of Osteopontin Chemosensitizes MDA-MB-231 Cells to Cyclophosphamide by Enhancing Apoptosis Through Activating p38 MAPK Pathway

Cyclophosphamide (CTX) is a commonly used chemotherapeutic agent for breast cancer. However, chemoresistance remains a common clinical problem. Osteopontin (OPN) has been shown to induce chemoresistance by inhibiting apoptosis; p38 MAPK pathway has been reported to be involved in chemotherapy-induced apoptosis. Thus, this study investigated whether OPN knockdown would chemosensitize MDA-MB-231 cells to CTX by enhancing apoptosis through activating p38 MAPK pathway. MDA-MB-231 cells were transfected with OPN stable siRNA plasmid, and it was found that OPN knockdown chemosensitized MDA-MB-231 cells to CTX, which is dependent on p38 MAPK pathway activation. Moreover, results showed that each of OPN knockdown and CTX could induce apoptosis through activating p38 MAPK pathway and that OPN knockdown and CTX could induce enhanced apoptosis through activating p38 MAPK pathway synergistically. Therefore, this study concludes that OPN knockdown chemosensitizes MDA-MB-231 cells to CTX by enhancing apoptosis through activating p38 MAPK pathway.

MiR-181b regulates cisplatin chemosensitivity and metastasis by targeting TGFβR1/Smad signaling pathway in NSCLC

MicroRNAs (miRNAs) have been identified as important post-transcriptional regulators involved in various biological and pathological processes of cells, but their underlying mechanisms in chemosensitivity and metastasis have not been fully elucidated. The objective of this study was to identify miR-181b and its mechanism in the chemosensitivity and metastasis of NSCLC. We found that miR-181b expression levels were lower in A549/DDP cells compared with A549 cells. Functional assays showed that the overexpression of miR-181b inhibited proliferation, enhanced chemosensitivity to DDP, attenuated migration and metastatic ability in NSCLC cell lines in vitro and in vivo. TGFβR1 was subsequently identified as a novel functional target of miR-181b. TGFβR1 knockdown revealed similar effects as that of ectopic miR-181b expression, whereas overexpression of TGFβR1 rescued the function of miR-181b-mediated growth, chemosensitivity and metastasis in NSCLC cells. In addition, miR-181b could inactivate the TGFβR1/Smad signaling pathway. We also observed that decreased miR-181b expression and increased TGFβR1 expression were significantly associated with chemosensitivity to DDP and tumor metastasis in NSCLC patients. Consequently, miR-181b functions as a tumor suppressor and has an important role in proliferation, chemosensitivity to DDP and metastasis of NSCLC by targeting TGFβR1/Smad signaling pathway.

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.

Tea polyphenols induced apoptosis of breast cancer cells by suppressing the expression of Survivin.

To study the mechanism of tea polyphenols (TP)-induced apoptosis of breast cancer cells. Proliferation of MCF-7 and SK-BR-3 cells was evaluated by MTT assays. Cellular ultrastructure was examined by electron microscopy. Apoptosis was detected by TUNEL. PCNA、 Cyclin D1、 Cyclin E and Survivin expression was measured by Western blot. Cell proliferation was significantly inhibited by TP. Spindle and round cells were loosely distributed with increased particles after TP treatment. Increased cell size, frequent nuclear atypia and a collapse of apoptosis were observed. The nucleus was pushed towards one side, while the cytoplasm was rich in free ribosome. The membrane of mitochondria was thickening, and the cell apoptotic body was observed. TP treated cells experienced significantly enhanced apoptosis compared with 5-Fu treated or control groups. The expression of survivin was downregulated by TP. To conclude, TP can inhibit cell growth and induce apoptosis through downregulating the expression of survivin in breast cancer.

USP22 promotes tumor progression and induces epithelial–mesenchymal transition in lung adenocarcinoma

OBJECTIVES Our previous study showed that USP22 as an oncogene may mediate cancer development and progression in NSCLC, but the underlying molecular mechanism remains uncharacterized. Epithelial-mesenchymal transition (EMT) has been reported to play an important role in migration and invasion of the tumor cells. Thus, this study aims to determine the clinical significance and the possible roles of USP22 in EMT and progression of lung adenocarcinoma. METHODS Immunohistochemistry was used to determine the expression of USP22 in clinical samples. The clinical correlations and prognostic significance of the aberrantly expressed proteins were evaluated by statistical analysis. Moreover, we evaluated whether USP22 could induce EMT in cultured lung cancer cells. RESULTS The USP22 expression was positive in 76.03% of specimens and was correlated with advanced clinicopathologic classifications (differentiation, T and AJCC stages) and TGF-β1 expression (p=0.008). Multivariate Cox regression analysis revealed that USP22 expression level was an independent prognostic factor for both overall survival and disease-free survival (HR, 2.060; p=0.013 and HR, 1.993; p=0.016). In vitro study revealed that USP22 can regulate proliferation and invasive properties, and induce EMT of lung adenocarcinoma cells. Moreover, USP22 may up-regulate TGF-β1 expression. CONCLUSIONS Our data indicated that USP22 may promote lung adenocarcinoma cell invasion by the induction of EMT.

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.

TRIM44 promotes proliferation and metastasis in non-small cell lung cancer via mTOR signaling pathway

Tripartite motif-containing protein 44 (TRIM44) was recently identified as a potential therapeutic target in several types of malignancy, but its effect on the clinical course of malignancy and its underlying regulatory mechanism remain largely unknown. The present study shows that upregulation of TRIM44 is associated with poor differentiation, advanced pTNM stage, adenocarcinoma subtype, lymph node metastasis and, most importantly, unfavorable survival in patients with non-small cell lung cancer (NSCLC). TRIM44 knockdown inhibited the invasion and migration of human NSCLC cells, which was concurrent with downregulation of mesenchymal markers and upregulation of epithelial markers. Overexpression of TRIM44 induced the epithelial-to-mesenchymal transition (EMT) and increased the metastatic potential of lung cancer cells. Additionally, TRIM44 induced cell proliferation in vitro and tumor growth in vivo by accelerating G1/S transition via upregulation of cyclins and CDKs. TRIM44-induced mTOR signaling, EMT, and cyclin/CDK upregulation were reversed by treatment with a mammalian target of rapamycin (mTOR) inhibitor. These results provide a model for the relationship between TRIM44 expression and lung cancer progression, and open up new avenues for the prognosis and therapy of lung cancer.