Propidium iodide staining suggested that most of them were dead cells. Additional microscopic analysis using anticleaved caspase antibody and by TUNEL assay indicated that treatment of lung cancer cells with antiDKK antibody induced apoptosis probably through proteolytic activation of caspase. B, elevated expression of DKK transcript in cancer cell lines. Over the last two decades, several candidate molecular targets and biomarkers for cancer therapy have been reported.However, suppression of some of the target molecules can provide survival benefits to a limited subset of the patients, and a few useful biomarkers are presently available.In order to identify molecules involved in pulmonary and esophageal carcinogenesis, and those useful as therapeutic targets and biomarkers for cancer, we have established an effective screening system and identified DKK as an oncoprotein whose upregulation is a frequent and important feature of the malignant nature of human cancers.In this study, we confirmed that DKK was highly expressed in cancers in various organs, but was hardly detectable in their adjacent normal tissues. To elucidate the possible mechanism of DKK overexpression in cancer cells, we cultured lung cancer A cells in the presence or absenceof aza deoxycyt id ine and exam ined DKK express ion. Treatment of NCIH cells with azadeoxycytidine induced DKK mRNA expression in a dosedependent manner, whereas that of A cells with azadeoxycytidine did not affect the level of DKK expression, implying that elevation of DKK expression in lung cancer cells is likely to be caused by some epigenetic alterations inc luding the loss of promoter methylation of the DKK gene. The cell growth of A cells detected using MTT assays was suppressed by addition of antiDKK antibody into their culture media, in a dosedependent manner, whereas that of NCIH was not affected.B, morphologic DPPC change of A cells induced by antiDKK antibody.C and D, induction of apoptosis of A cells treated with antiDKK antibody.At day, a fibrotic change and more significant decrease of viable cancer cells were observed.DKK protein in serologic samples from patients having cancers at an early or advanced disease stage in either of six organs.Although further validation using a larger set of serum samples covering various clinical stages will be required, our data presented here also indicate a potential clinical usefulness of DKK as a serologic biomarker for NSCLC that could be widely used in clinical practice, such as detection of cancer, prediction of the malignant potential of tumor, and monitoring the disease condition after any anticancer treatment.The evidence we showed here clearly imply that DKK is likely to be involved in critical steps of tumor growthmetastasis.We also found the possible inhibitory effect of antiDKK antibody on cell invasion and growth.With the advances in understanding aberrant signa ling pathways in various types of cancer, many pivotal regulators of malignant behavior of cancer cells have emerged as candidates for molecular targetbased therapy.Recently, a few groups reported the usefulness of antiDKK antibody for preventing bone absorption in some disease conditions.The role of DKK in progression of bone lesions has also been studied in prostate cancer; transfection of DKK into the osteoblastic prostate cancer cell line CB, which normally induces a mix of osteoblastic and osteolytic lesions, caused the cells to develop osteolytic tumors in severe combined immunodeficient mice.

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