Shaohao Luo,Yunfei Bai,Boqian Wang,Haixia Xu,Shu Zhang,Gang Guo,Xin Li,Hongyang Sun,Xiaobo Cui
Homeobox A1 (HOXA1) is implicated in the progression of various cancers, but its biological function in laryngeal cancer (LC) remains undefined, which is the foothold of our study. Bioinformatics analysis and survival analysis were performed to predict HOXA1 expression in LC tissues, and the prognostic relationship between high HOXA1 expression and LC. Whether high HOXA1 expression correlated with the clinical characteristics and prognosis of LC patients was analyzed. LC cell viability and sensitivity to cisplatin were determined by Methyl thiazolyl tetrazolium assay. The cell migration, invasion, and cell cycle after transfection were examined by Wound healing, Transwell, and flow cytometry assays, respectively. The corresponding mRNA and protein expressions were measured by quantitative real-time PCR or Western blot. A higher expression of HOXA1 was detected in LC tissues, which was found to be relevant to poor prognosis of LC patients. The association of high expression of HOXA1 with lymph node and clinical stage was also confirmed. Silencing of HOXA1 in LC cells enhanced the cell sensitivity to cisplatin, inhibited viability, migration, invasion and cell cycle, and reduced N-Cadherin, Vimentin, PCNA, p-AKT and p-mTOR expressions, while overexpression of HOXA1 had the opposite effects. Collectively, HOXA1 boosts migration, invasion and cell cycle, while suppressing cisplatin sensitivity of LC cells by mediating AKT/mTOR pathway, hinting that HOXA1 is a promising biomarker for diagnosis and prognosis of LC in clinical practice.
Han Zhiyang,Hu Haidi,Yin MingZhu,Lin Yu,Yan Yan,Han Peng,Liu Bing,Jing Bao
Background Macrophage-like transformation of vascular smooth muscle cells (VSMCs) is a risk factor of atherosclerosis (AS) progression. Transcription factor homeobox A1 (HOXA1) plays functional roles in differentiation and development. This study aims to explore the role of HOXA1 in VSMC transformation, thereby providing evidence for the potential mechanism of AS pathogenesis.Methods High fat diet (HFD)-fed apolipoprotein E knockout (ApoE−/−) mice were applied as an in vivo model to imitate AS, while 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POV-PC)-treated VSMCs were applied as an in vitro model. Recombinant adeno-associated-virus-1 (AAV-1) vectors that express short-hairpin RNAs targeting HOXA1, herein referred as AAV1-shHOXA1, were generated for the loss-of-function experiments throughout the study.Results In the aortic root of AS mice, lipid deposition was severer and HOXA1 expression was higher than the wide-type mice fed with normal diet or HFD. Silencing of HOXA1 inhibited the AS-induced weight gain, inflammatory response, serum and liver lipid metabolism disorder and atherosclerotic plaque formation. Besides, lesions from AS mice with HOXA1 knockdown showed less trans-differentiation of VSMCs to macrophage-like cells, along with a suppression of krüppel-like factor 4 (KLF4) and nuclear factor (NF)-κB RelA (p65) expression. In vitro experiments consistently confirmed that HOXA1 knockdown suppressed lipid accumulation, VSMC-to-macrophage phenotypic switch and inflammation in POV-PC-treated VSMCs. Mechanism investigations further illustrated that HOXA1 transcriptionally activated RelA and KLF4 to participate in the pathological manifestations of VSMCs.Conclusion sHOXA1 participates in AS progression by regulating VSMCs plasticity via regulation of NF-κB p65 and KLF4. HOXA1 has the potential to be a biomarker or therapeutic target for AS.
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