| Backgrounds and objectives:Cancer cells respond to unfavorable microenvironments such as oxidative stress andhypoxia by comprehensive metabolic reprogramming. More than half a century ago, OttoWarburg noted that cancer cells use aerobic glycolysis with reduced mitochondrialoxidative phosphorylation for glucose metabolism to adapt to hypoxia, called ‘Warburgeffect’. One compelling idea to explain the effect is that the altered metabolism of cancercells confers a selective advantage for survival and proliferation in the unique cancermicroenvironment. Mitochondrion is believed to be linked to this complex adaptiveresponse and emerging evidences indicate that UCP2(uncoupling proteins2), amitochondrial inner membrane anion carrier, and HIF1α (transcriptional complexhypoxia-inducible factor1α), the key regulator of the hypoxic response, may contribute tothis process.As the early tumor expands, it outgrows the diffusion limits of its local blood supply,leading to hypoxia and ischemia. Effects of UCP2and HIF1α on mitochondrialbioenergetics and redox homeostasis in cancer cells may mediate a wide range ofphysiological and cellular mechanisms necessary to adapt reduced oxygen supply, cellgrowth and proliferation, apoptosis and enhancing robustness.This mechanism may accountfor the protective effects of UCP2and HIF1α in cancer cells that exhibit the Warburg effect.According to our observations and speculation, cancer cells may use UCP2in theirmetabolic adaptation to avoid ROS-mediated apoptosis. UCP2overexpression may protecta wide array of cell types from apoptosis and that the cytoprotective effect of UCP2islikely based on reduction of mitochondrial ROS generation. As a consequence, themitochondrial oxygen-consumption is downregulated and hypoxic ROS generation isattenuated. Activation of glycolytic genes by HIF1α is considered critical for metabolicadaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. These studies reveal a hypoxia-induced metabolic switch thatshunts glucose metabolites from the mitochondria to glycolysis to maintain ATP productionand to prevent toxic ROS production.Despite the functional overlap of UCP2and HIF1α, there is currently no experimentaldata to substantiate an association between UCP2and HIF1α and potential implications fortheir biology of cancer cells remain speculative. Further studies will be necessary todelineate the precise molecular mechanisms by which UCP2and HIF1α contributes to therobustness of cancer and to determine whether UCP2is feasible targets for novelanti-cancer strategies.Materials and Methods1Cases materialsSurgical samples of54patients with primary lung cancer and54adjacenthistologically normal lung tissue samples were obtained from the Xinqiao hospital of thethird military medical university in2010-12～2011-3,which contains30male cases and24female cases. Median age was54years (range48–79). The surgical specimens of lungcancers include squamous cell carcinoma (n=18) and adenocarcinoma (n=36). None of thepatients recruited into the study had a known history of industrial or occupational exposureto asbestos or organic solvent. All the tissues were kept in liquid nitrogen immediately aftersurgical resection according to a protocol, which were in accordance with the ethicalstandards of the responsible committee for conducting human research at the hospital andwith the Helsinki Declaration of1975, as revised in2000.2Methods(1)The mRNA of UCP2and HIF1α were detected by Quantitative RT-PCR.(2) The UCP2was detected by Western blotting.(3) The UCP2was detected by Immunohistochemistry.Results:1The levels of UCP2and HIF1α mRNA as measured in paired surgical specimens oflung cancer and peritumoral tissue and expressed as T/P ratios are2.97and3.97respectively, have significant differences.(P<0.01).2The relevant analysis of HIF1α and UCP2mRNA expression in lung cancer groupshowed no significant correlation, the difference was not statistically significant.(P>0.05). 3The analysis of UCP2protein expression in human lung cancer and peritumoraltissue by Western blotting showed statistically significant(P<0.01).4Immunohistochemical assessment of UCP2expression in human lung cancer andperitumoral tissue showed they were mainly in the cytoplasm of lung cancer cells, a tanuniform dyeing, dyeing rate is high and strong positive, and the expression for dyeing ismoderate and strong positive primarily.Conclusions:1The mRNA expression of UCP2and HIF1α are both increased in human lungcancers, may be involved in tumor progression in lung carcinoma.2UCP2mRNA levels showed no significant correlation with increased HIF1α mRNAin lung cancer cells.3The expression of UCP2was not significantly associated with differentiation andappears to correlate with clinical stages and pathology classification of lung cancer. |
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