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Acidosis, regardless of hypoxia involvement, is recognized as a chronic and harsh tumor microenvironment (TME) that educates malignant cells to thrive and metastasize. Although overwhelming evidence supports an acidic environment as a driver or ubiquitous hallmark of cancer progression, the unrevealed core mechanisms underlying the direct effect of acidification on tumorigenesis have hindered the discovery of novel therapeutic targets and clinical therapy. Here, chemical-induced and transgenic mouse models for colon, liver and lung cancer were established, respectively. miR-7 and TGF-β2 expressions were examined in clinical tissues (n = 184). RNA-seq, miRNA-seq, proteomics, biosynthesis analyses and functional studies were performed to validate the mechanisms involved in the acidic TME-induced lung cancer metastasis. Our data show that lung cancer is sensitive to the increased acidification of TME, and acidic TME-induced lung cancer metastasis via inhibition of miR-7-5p. TGF-β2 is a direct target of miR-7-5p. The reduced expression of miR-7-5p subsequently increases the expression of TGF-β2 which enhances the metastatic potential of the lung cancer. Indeed, overexpression of miR-7-5p reduces the acidic pH-enhanced lung cancer metastasis. Furthermore, the human lung tumor samples also show a reduced miR-7-5p expression but an elevated level of activated TGF-β2; the expressions of both miR-7-5p and TGF-β2 are correlated with patients' survival. We are the first to identify the role of the miR-7/TGF-β2 axis in acidic pH-enhanced lung cancer metastasis. Our study not only delineates how acidification directly affects tumorigenesis, but also suggests miR-7 is a novel reliable biomarker for acidic TME and a novel therapeutic target for non-small cell lung cancer (NSCLC) treatment. Our study opens an avenue to explore the pH-sensitive subcellular components as novel therapeutic targets for cancer treatment.
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@#Introduction: Meloxicam is a NSAID which able to inhibit the cyclooxygenase 2 (COX-2). The purpose of this research is to explain the effect of Meloxicam in inhibit the growth of oral squamous cell carcinoma (OSCC) induced by benzopyrenes. The apoptosis and proliferation of OSCC, the p53, Ras and COX-2 expression used as indicator. Methods: male mice were induced by benzopyrene 10 mg/kg body weight was given topically on buccal mucosa 2 times a week for 4 weeks for induced the OSCC. Meloxicam was given orally with 3 different doses was 50mg/kg, 100mg/kg, and 200mg/kg.b.w given once a day for 60 days. The control groups were given with CMC-1% 0.1ml/10g body weight. The buccal mucosa then biopsy and staining with immunohistochemistry to analyzed the p53, Ras, COX-2 expression, apoptosis and proliferation of OSCC. Results: The increase of Meloxicam dose is proportional to the increase in wild p53 expression and apoptosis, and inversely proportional to the expression of mutant race, cox-2 and the proliferation of OSCC. Conclusion: Meloxicam able to inhibit the growth of OSCC induced by benzopyrenes.
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Objective To investigate the influence of benzopyrene on extracellular matrix(ECM) protein deposition of human airway smooth muscle cells(HASMC) and the related pathway mechanism.Methods HASMC were primarily cultured and the 2-6 generations cells were applied in this experiment.The expression amount of ECM gene and protein was detected by real time PCR and Western Blot the phosphorylation level was analyzed by using the Western Blot method.Results Benzopyrene could to increase the expression of HASMC collagen Ⅰ α1 protein (P＜0.01) and ECM protein (including collagen Ⅰ α1,versican,fibronectin,laminin α2) mRNA(P＜0.05).Benzopyrene could induce the rapid increase of ERK1/2 phosphorylation level (P＜0.01).Furthermore,the ERK pathway inhibitor PD98059 could significantly inhibit the increase of benzopyrene-induced collagen Ⅰ α1 (P＜0.01)and ECM protein(including collagen Ⅰ α1,versican,fibronectin,laminin α2) mRNA expression(P＜0.01).Conclusion Benzopyrene induces the ECM protein deposition of HASMC by activating the ERK1/2 pathway,blocking the ERK1/2 signal pathway can inhibit the benzopyrene-induced airway remodeling.
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Objective To investigate the feasibility of pig lung cancer model induced by bronchial perfusion of 3,4-benzopyrene. Methods 24 experimental pig were randomly divided into model group and control group, each containing 12 cases. Experimental pigs were under the anaesthetic state, pigs in the model group were given endobronchial infusion of 3,4 - benzopyrene - corn oil mixture, pigs in control group were injected with equal capacity of corn oil.Perfusion 1 times a week for 16 weeks.In week 16,32 and 48,all experimental pig were given lung CT scans, then the lung lesions were observed.After 48 weeks, the pig lung, esophagus, and gastrointestinal tract, liver and brain and other organs were dissected, the presence of tumor formation was observed, and the mass, and experimental pig lung biopsy were given hematoxylin and eosin staining analysis. Results Lung cancers were not found in control group by both CT lung cancers and anatomy. In the model group, pulmonary CT showed space-occupying lesions with different location and size in lungs of 8 pigs, and the space-occupying lesions were confirmed as malignant tumors by pathology, including 3 cases of moderately differentiated adenocarcinoma, 2 cases of highly differentiated squamous cell carcinoma, 1 case of alveolar cell carcinoma,2 cases of adenosquamous carcinoma. Three other pigs and pigs in the control group were not found with tumor by both lung CT and anatomy. Pigs in model group were induced successfully to malignant tumor in 1 year , the total tumor formation rate was 75%,lung tumor formation rate was 66.66%. Conclusion The trachea bronchial perfusion of 3,4- benzopyrene is a simple,safe and reliable way to construct animal models of lung cancer.
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BACKGROUND: Cigarette smoking is an important risk factor for chronic bronchitis and COPD. Airway epithelial cells exposed to cigarette smoke components such as nicotine, cotinine and benzopyrene can generate reactive oxygen species (ROS) and be subject to oxidative stress. This oxidative stress can induce the inflammatory response in the lung by the oxidant itself or by the release of proinflammatory cytokines. It has been reported that nicotine stimulates ROS, which are associated with NF-kappaB. METHODS: Beas2B cells were treated with nicotine, cotinine and benzopyrene. RT PCR was used to measure the expression of several antioxidant factors using the total RNA from the Beas2B cells. The level of superoxide dismutase(CuZnSOD), thioredoxin, glutathione reductase expression was examined. RESULTS: 0.5 to 4 hours after the benzopyrene, nicotine and cotinine theatments, the level of thioredoxin and glutathione reductase expression decreased. Longer exposure to these compounds for 24 to 72 hours inhibited the expression of most of these antioxidant factors. CONCLUSION: During exposure to smoke compounds, thioredoxin and glutathione reductase are the key antioxidant factors induced sensitively between 0.5 and 4 hours but the levels these antioxidants decrease between 24 hour and 72hours.