Project description:Extracellular pH (pHe) is lower in many tumors than in the corresponding normal tissue. Acidic tumor microenvironment has been shown to facilitate epithelial mesenchymal transition (EMT) and tumor metastasis, while the mechanisms underlying tumor acidic microenvironment-induced tumor cell metastasis remain undefined. Here, we aimed to investigate the tumor metastasis and the EMT by acidic microenvironment and to explore their mechanisms and clinical significance in lung cancer. Results showed that acidic pHe remarkably enhanced invasion ability of lung cells accompanying with increased mesenchymal and decreased epithelial markers. Moreover, acidic pHe triggered the inhibition of microRNA-7 (miR-7) expression and activation of TGF-β2/SMAD signaling. Mechanistic studies showed that TGF-β2 is a direct potential target gene of miR-7, and acidity-induced metastasis could be abolished by treatment with a TGFβRI inhibitor, anti-TGF-β2 antibody and miR-7 mimic, respectively. The clinical samples further revealed that miR-7 was decreased in lung tissues and antagonistically correlated with TGF-β2 expression, associating with overall survival and metastasis. In conclusion, our study indicated that acidic pHe showed enhanced invasive potential, and enhanced potential to develop experimental metastases by a novel mechanism involving tumor acidic microenvironment-induced regulation of miR-7/TGF-β2/SMAD axis. Our findings suggest that the possibility that pHe of the primary tumor may be an important prognostic parameter for lung cancer patients merit clinical investigation. Moreover, miR-7 may serve as prognostic molecular marker and a novel therapeutic target for lung cancer.
Project description:To investigate the genes that are modulated by acidic extracellular pH, we treated the mouse B16-BL6 cells with acidic medium and then analyzed them comprehensively by cDNA microarray.
Project description:Transcriptional profiling of Candida albicans cells grown under planktonic and biofilm-inducing conditions, comparing SN76 and sfl1Δ/sfl1Δ strains. Goal was to study the effect of SFL1 deletion on the transcriptomic profile of C. albicans planktonic and biofilm cells under acidic conditions, in order to reveal the function of the Sfl1 transcription factor in C. albicans biofilm development.
Project description:Many solid tumors grow slowly, with an average volume doubling time of several months to multiple years. Yet, most studies to date have focused mainly on the short-term fate of cancerous cells upon exposure to acidic pHe (extracellular pH), a common hallmark of tumor microenvironment. Little is known about how solid tumors, such as intractable PDAC originated from pancreatic ductal cells that secrete alkaline fluids, evolve to tolerate and adapt to the sustained and prolonged exposure of acidic pHe stress. We established a series of PDAC tumor cells exposed to prolonged periods of extracellular acidification. These biological materials were further subjected to microarray analysis to detail the genome-wide gene expression profiles and to identify the differential expressed genes related to the long-term adaptation of PDAC tumor cells to the extracellular chronic acidosis stress.
Project description:Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the USA, accounting for ~40,000 deaths annually. The dismal prognosis for PDAC is largely due to its late diagnosis. Currently, the most sensitive diagnosis of PDAC requires invasive procedures, such as endoscopic ultrasonography, which has inherent risks and accuracy that is highly operator dependent. Here we took advantage of a general characteristic of solid tumors, the acidic microenvironment that is generated as a by-product of metabolism, to develop a novel approach of using pH (Low) Insertion Peptides (pHLIPs) for imaging of PDAC. We show that fluorescently labeled pHLIPs can localize and specifically detect PDAC in human xenografts as well as PDAC and PanIN lesions in genetically engineered mouse models. This novel approach may improve detection, differential diagnosis and staging of PDAC.