EGFR is a potent stimulator of invasion and metastasis in head and neck squamous cell carcinomas (HNSCC). However, the mechanism by which EGFR may stimulate tumor cell invasion and metastasis still need to be elucidated. In this study, we showed that activation of EGFR by EGF in HNSCC cell line SCC10A enhanced cell migration and invasion, and induced loss of epitheloid phenotype in parallel with downregulation of E-cadherin and upregulation of N-cadherin and vimentin, indicating that EGFR promoted SCC10A cell migration and invasion possibly by an epithelial to mesenchymal transition (EMT)-like phenotype change. Interestingly, activation of EGFR by EGF induced production of matrix metalloproteinase-9 (MMP-9) and soluble E-cadherin (sE-cad), and knockdown of MMP-9 by siRNA inhibited sE-cad production induced by EGF in SCC10A. Moreover, both MMP-9 knockdown and E-cadherin overexpression inhibited cell migration and invasion induced by EGF in SCC10A. The results indicate that EGFR activation promoted cell migration and invasion through inducing MMP-9-mediated degradation of E-cadherin into sE-cad. Pharmacologic inhibition of EGFR, MEK, and PI3K kinase activity in SCC10A reduced phosphorylated levels of ERK-1/2 and AKT, production of MMP-9 and sE-cad, cell migration and invasion, and expressional changes of EMT markers (E-cadherin and N-cadherin) induced by EGF, indicating that EGFR activation promotes cell migration and invasion via ERK-1/2 and PI3K-regulated MMP-9/E-cadherin signaling pathways. Taken together, the data suggest that EGFR activation promotes HNSCC SCC10A cell migration and invasion by inducing EMT-like phenotype change and MMP-9-mediated degradation of E-cadherin into sE-cad related to activation of ERK-1/2 and PI3K signaling pathways.

Hypoxia-inducible factor (HIF) is a main heterodimeric transcription factor that regulates the cellular adaptive response to hypoxia by stimulating the transcription of a series of hypoxia-inducible genes. HIF is frequently upregulated in solid tumors, and the overexpression of HIF can promote tumor progression or aggressiveness by blood vessel architecture and altering cellular metabolism. In this review, we focused on the pivotal role of HIF in tumor angiogenesis and energy metabolism. Furthermore, we also emphasized the possibility of HIF pathway as a potential therapeutic target in cancer.

Hypoxia is a key component of the tumor microenvironment and represents a well-documented source of therapeutic failure in clinical oncology. Recent work has provided support for the idea that non-coding RNAs, and in particular, microRNAs, may play important roles in the adaptive response to low oxygen in tumors. Specifically, all published studies agree that the induction of microRNA-210 (miR-210) is a consistent feature of the hypoxic response in both normal and malignant cells. miR-210 is a robust target of hypoxia-inducible factors, and its overexpression has been detected in a variety of diseases with a hypoxic component, including most solid tumors. High levels of miR-210 have been linked to an in vivo hypoxic signature and to adverse prognosis in breast and pancreatic cancer patients. A wide variety of miR-210 targets have been identified, pointing to roles in mitochondrial metabolism, angiogenesis, DNA damage response, apoptosis, and cell survival. Such targets are suspected to affect the development of tumors in multiple ways; therefore, an increased knowledge about miR-210's functions may lead to novel diagnostic and therapeutic approaches in cancer.

To discover novel biomarkers for early detection of human lung squamous cell cancer (LSCC) and explore possible mechanisms of LSCC carcinogenesis, iTRAQ-tagging combined with two dimensional liquid chromatography tandem MS analysis was used to identify differentially expressed proteins in human bronchial epithelial carcinogenic process using laser capture microdissection-purified normal bronchial epithelium (NBE), squamous metaplasia (SM), atypical hyperplasia (AH), carcinoma in situ (CIS) and invasive LSCC. As a result, 102 differentially expressed proteins were identified, and three differential proteins (GSTP1, HSPB1 and CKB) showing progressively expressional changes in the carcinogenic process were selectively validated by Western blotting. Immunohistochemistry was performed to detect the expression of the three proteins in an independent set of paraffinembedded archival specimens including various stage tissues of bronchial epithelial carcinogenesis, and their ability for early detection of LSCC was evaluated by receiver operating characteristic analysis. The results showed that the combination of the three proteins could perfectly discriminate NBE from preneoplastic lesions (SM, AH and CIS) from invasive LSCC, achieving a sensitivity of 96% and a specificity of 92% in discriminating NBE from preneoplatic lesions, a sensitivity of 100% and a specificity of 98% in discriminating NBE from invasive LSCC, and a sensitivity of 92% and a specificity of 91% in discriminating preneoplatic lesions from invasive LSCC, respectively. Furthermore, we knocked down GSTP1 in immortalized human bronchial epithelial cell line 16HBE cells, and then measured their susceptibility to carcinogen benzo ( Lung cancer is the most frequently occurring malignancy with increasing incidence and is the leading cause of mortality in cancer-related deaths in China and worldwide (1, 2). Although great improvement has been made in diagnosis and treatment of lung cancer, the overall patients' survival is still very low and does not exceed 15% (3). The poor prognosis of this cancer is mainly explained by the fact that the diagnosis is generally made only at advanced stages because of the lack of reliable, early diagnostic biomarkers and the limited understanding of its carcinogenic mechanisms. Therefore, identification of biomarkers for early detection of lung cancer is mandatory, in turn leading to more effective treatment and reduction of mortality.Lung squamous cell carcinoma (LSCC) 1 originated from the bronchial epithelial cells is the most common histological type of lung cancer. It is known that carcinogenesis of LSCC is a multistage process and the result of multistep accumulation of genetic and epigenetic alterations (4). With exposure to environmental carcinogens, bronchial epithelial carcinogenesis often progresses in the following manner: hyperplasia, squamous metaplasia (SM), atypical hyperplasia (AH), cancer in situ (CIS) and invasive cancer (5). LSCC is the end-point of a whole range of morphological abnormalities that are dis-...

Tamoxifen is a drug commonly used in the treatment of breast cancer, especially for postmenopausal patients. However, its efficacy is limited by the development of drug resistance. Downregulation of estrogen receptor alpha (ERα) is an important mechanism of tamoxifen resistance. In recent years, with progress in research into the protective autophagy of drug-resistant cells and cell cycle regulators, major breakthroughs have been made in research on tamoxifen resistance. For a better understanding of the mechanism of tamoxifen resistance, protective autophagy, cell cycle regulators, and some transcription factors and enzymes regulating the expression of the estrogen receptor are summarized in this review. In addition, recent progress in reducing resistance to tamoxifen is reviewed. Finally, we discuss the possible research directions into tamoxifen resistance in the future to provide assistance for the clinical treatment of breast cancer.

The purpose of this study is to explore the role of hypoxia on the invasion and metastasis of laryngeal carcinoma. The invasion and migration ability of laryngeal cancer SCC10A cell was detected by transwell assay. Western blot was applied to analyze the expression of EMT-related proteins. Fifty-seven samples from postoperative patients with laryngeal cancer were collected to study. Immunohistochemistry was used to examine the expression of GLUT-1 and EMT-related proteins (Vim, E-cad, N-cad) in normal laryngeal squamous epithelial tissue, laryngeal cancer adjacent tissues and laryngeal squamous cell carcinoma tissues. Hypoxia promoted laryngeal cancer cell invasion and migration. Hypoxia also enhanced the expression of GLUT-1, vimentin and N-cad, which exist statistically significant correlation with the clinical staging and lymph node metastases (P < 0.05). The expression of GLUT-1 is positively correlated with Vim and N-cad expression in laryngeal squamous cell carcinoma tissues, but negatively correlated with E-cad expression. The patient survival rate with the positive expression of GLUT-1, Vim and N-cad becomes much shorter compared with those with negative expression of GLUT-1, Vim and N-cad (P < 0.05). Hypoxia promoted laryngeal cancer cell invasion and migration via EMT.

Evidence shows that Bcl-2 family members play a direct role in the development of some human malignancies. However, the mechanism by which Bcl-2 may influence tumor cell invasion and metastasis remains unclear. Ectopic overexpression of Bcl-2 in the human squamous carcinoma cell line HSC-3 enhanced tumorigenicity and experimental pulmonary metastasis. Interestingly, Bcl-2-expressing cells showed morphologic changes that resembled that of cells with an epithelial-mesenchymal transition phenotype. Analysis revealed increased N-cadherin and vimentin expression in parallel with attenuated E-cadherin level, along with enhanced migration and invasive behavior. Zymography studies confirmed elevated levels of matrix metalloproteinase-9 (MMP-9) in media of Bcl-2-expressing cells. siRNA-mediated suppression of N-cadherin expression not only prevented the enhanced invasion but also blocked the increased MMP-9 expression induced by elevated Bcl-2 expression. Accordingly, pharmacologic inhibition of MMP-9 abrogated the increased tumor cell invasion. Furthermore, the Bcl-2-mediated increase in MMP-9 expression and tumor cell invasion was dependent on fibroblast growth factor receptor-1 or extracellular signal-regulated kinase signaling. Collectively, the data establish that Bcl-2 overexpression in squamous carcinoma cells induces a partial epithelial to mesenchymal transition that promotes not only survival but also invasion and metastasis through the N-cadherin/fibroblast growth factor receptor/extracellular signal-regulated kinase pathway. Mol Cancer Res; 8(2); 170-82. ©2010 AACR.

The microRNA hsa-miR-210 (miR-210) is associated with hypoxia; however its function has not fully identified. In the present study, we aim to detect its role concerning proliferation in Laryngocarcinoma. We found that miR-210 was highly expressed in hypoxia, which inhibited proliferation by inducing cell cycle arrest in G1/G0 as well as apoptosis. We further identified that miR-210 targeted fibroblast growth factor receptor-like 1 (FGFRL1). Down regulation of FGFRL1 decreased cell proliferation by promoting proportion of cells in G1/G0 phase and decreasing in S and G2/M phases. Moreover, overexpression of FGFRL1 effectively released the miR-210-induced suppression of SCC10A cell proliferation. Expression of miR-210 repressed tumor xenograft growth in vivo as well. Together, our findings reveal a new mechanism of adaptation to hypoxia that miR-210 inhibits the proliferation via inducing cell cycle arrest and apoptosis by the targeting of FGFRL1. J. Cell. Biochem. 116: 1039-1049, 2015. © 2015 Wiley Periodicals, Inc.