Serum OPN levels could be used as a biomarker for the early diagnosis of osteoporosis in postmenopausal women.

BACKGROUNDLung cancer is the leading cause of cancer death in Taiwan, and the paucity of dependable risk markers has impeded the early management of lung cancer. An association of human papillomavirus (HPV) 16/18 infection with lung cancer among nonsmoking Taiwanese women was revealed in our previous study.METHODSNested PCR was employed to detect HPV 16/18 DNA in the blood circulation of 149 lung cancer patients and 174 noncancer controls. In addition, correlation of prevalence of HPV DNA between the blood circulation and lung tumor tissue was compared from 70 sets of paired tumor tissues and peripheral blood samples available.RESULTSThe results showed that the prevalence rate of HPV 16/18 in the blood circulation of lung cancer cases was significantly higher than that of noncancer controls (47.7% vs. 12.6% for HPV 16, P < 0.0001; 30.9% vs. 5.2% for HPV 18, P < 0.0001). A significantly higher HPV 16 prevalence was detected in female lung cancer patients than that of male (57.6% vs. 41.1%, P = 0.048), as well as in cases with tumor Stages III/IV than those with tumor Stages I/II (54.6% vs. 29.3%, P = 0.006). After adjusting the effects of age, gender, and smoking status, a 6.5‐fold greater risk of lung cancer was demonstrated for those subjects with HPV Type 16 positive (95% CI 3.7–11.3, P < 0.0001), a 9.2‐fold for HPV Type 18 positive (95% CI 4.2–20.2, P < 0.0001), and a 75.7‐fold greatest risk for those with both HPV Type 16 and 18 positive (95% CI 9.8–582.1, P < 0.0001).CONCLUSIONSThese results suggested that the presence of HPV DNA in the blood circulation may serve as a feasible risk marker of lung cancer. Cancer 2003;97:1558–63. © 2003 American Cancer Society.DOI 10.1002/cncr.11191

Paxillin (PXN) is required for receptor tyrosine kinase-mediated ERK activation, and the activation of the Raf/MEK/ERK cascade has been linked with Bcl-2 expression. We hypothesized that phosphorylation of PXN by the EGFR/Src pathway might contribute to cisplatin resistance via increased Bcl-2 expression. We show that cisplatin resistance was dependent on PXN expression, as evidenced by PXN overexpression in TL-13 and TL-10 cells and PXN knockdown in H23 and CL1-5 cells. Specific inhibitors of signaling pathways indicated that the phosphorylation of PXN at Y118 and Y31 via the Src pathway was responsible for cisplatin resistance. We further demonstrated that ERK activation was also dependent on this PXN phosphorylation. Bcl-2 transcription was upregulated by phosphorylated PXN-mediated ERK activation via increased binding of phosphorylated CREB to the Bcl-2 promoter. A subsequent increase in Bcl-2 levels by a PXN/ERK axis was responsible for the resistance to cisplatin. Animal models further confirmed the findings of in vitro cells indicating that xenograft tumors induced by TL-13-overexpressing cells were successfully suppressed by cisplatin combined with Src or ERK inhibitor compared with treatment of cisplatin, Src inhibitor or ERK inhibitor alone. A positive correlation of phosphorylated PXN with phosphorylated ERK and Bcl-2 was observed in lung tumors from NSCLC patients. Patients with tumors positive for PXN, phosphorylated PXN, phosphorylated ERK and Bcl-2 more commonly showed a poorer response to cisplatin-based chemotherapy than did patients with negative tumors. Collectively, PXN phosphorylation might contribute to cisplatin resistance via activating ERK-mediated Bcl-2 transcription. Therefore, we suggest that Src or ERK inhibitor might be helpful to improve the sensitivity for cisplatin-based chemotherapy in NSCLC patients with PXN-positive tumors.

There is a wide range of drugs and combinations under investigation and/or approved over the last decade to treat colorectal cancer (CRC), but the 5-year survival rate remains poor at stages II-IV. Therefore, new, more-efficient drugs still need to be developed that will hopefully be included in first-line therapy or overcome resistance when it appears, as part of second- or third-line treatments in the near future. In this study, we revealed that heat shock protein 90 (Hsp90) inhibitors have high therapeutic potential in CRC according to combinative analysis of NCBI's Gene Expression Omnibus (GEO) repository and chemical genomic database of Connectivity Map (CMap). We found that second generation Hsp90 inhibitor, NVP-AUY922, significantly downregulated the activities of a broad spectrum of kinases involved in regulating cell growth arrest and death of NVP-AUY922-sensitive CRC cells. To overcome NVP-AUY922-induced upregulation of survivin expression which causes drug insensitivity, we found that combining berberine (BBR), a herbal medicine with potency in inhibiting survivin expression, with NVP-AUY922 resulted in synergistic antiproliferative effects for NVP-AUY922-sensitive and -insensitive CRC cells. Furthermore, we demonstrated that treatment of NVP-AUY922-insensitive CRC cells with the combination of NVP-AUY922 and BBR caused cell growth arrest through inhibiting CDK4 expression and induction of microRNA-296-5p (miR-296-5p)-mediated suppression of Pin1-β-catenin-cyclin D1 signaling pathway. Finally, we found that the expression level of Hsp90 in tumor tissues of CRC was positively correlated with CDK4 and Pin1 expression levels. Taken together, these results indicate that combination of NVP-AUY922 and BBR therapy can inhibit multiple oncogenic signaling pathways of CRC.