Ovarian cancer has one of the highest mortalities in malignancies in women, but little is known of its tumour progression properties and there is still no effective molecule that can monitor its growth or therapeutic responses. MSLN (mesothelin), a secreted protein that is overexpressed in ovarian cancer tissues with a poor clinical outcome, has been previously identified to activate PI3K (phosphoinositide 3-kinase)/Akt signalling and inhibit paclitaxel-induced apoptosis. The present study investigates the correlation between MSLN and MMP (matrix metalloproteinase)-7 in the progression of ovarian cancer, and the mechanism of MSLN in enhancing ovarian cancer invasion. The expression of MSLN correlated well with MMP-7 expression in human ovarian cancer tissues. Overexpressing MSLN or ovarian cancer cells treated with MSLN showed enhanced migration and invasion of cancer cells through the induction of MMP-7. MSLN regulated the expression of MMP-7 through the ERK (extracellular-signal-regulated kinase) 1/2, Akt and JNK (c-Jun N-terminal kinase) pathways. The expression of MMP-7 and the migrating ability of MSLN-treated ovarian cancer cells were suppressed by ERK1/2- or JNK-specific inhibitors, or a decoy AP-1 (activator protein 1) oligonucleotide in in vitro experiments, whereas in vivo animal experiments also demonstrated that mice treated with MAPK (mitogen-activated protein kinase)/ERK- or JNK-specific inhibitors could decrease intratumour MMP-7 expression, delay tumour growth and extend the survival of the mice. In conclusion, MSLN enhances ovarian cancer invasion by MMP-7 expression through the MAPK/ERK and JNK signal transduction pathways. Blocking the MSLN-related pathway could be a potential strategy for inhibiting the growth of ovarian cancer.

Mesothelin, a secreted protein, is overexpressed in some cancers, but its exact function remains unclear. The aim of the present study was to evaluate the possible function of mesothelin. Real-time PCR, RT (reverse transcription)-PCR, cytotoxicity assays, proliferative assays, apoptotic assays by Hoechst staining, detection of active caspases 3 and 7 by flow cytometric analysis, and immunoprecipitation and immunoblotting were performed. Cancer tissues in paclitaxel-resistant ovarian cancer patients expressed higher levels of mesothelin as assessed using real-time PCR than paclitaxel-sensitive ovarian cancer patients (the mean crossing point value change of mesothelin was 26.9+/-0.4 in the resistant group and 34.3+/-0.7 for the sensitive group; P<0.001). Mesothelin also protected cells from paclitaxel-induced apoptosis. The protein expression of Bcl-2 family members, such as Bcl-2 and Mcl-1, was significantly increased regardless of whether cells were treated with exogenous mesothelin or were mesothelin-transfectants. Furthermore, mesothelin-treated cells revealed rapid tyrosine phosphorylation of the p85 subunit of PI3K (phosphoinositide 3-kinase) and ERK (extracellular-signal-regulated kinase) 1/2 for enhancing MAPK (mitogen-activated protein kinase) activity. The anti-apoptotic ability was suppressed and the expression of Bcl-2 family in response to mesothelin was altered by inhibiting PI3K activity, but not by inhibiting MAPK activity. Thus mesothelin can inhibit paclitaxel-induced cell death mainly by involving PI3K signalling in the regulation of Bcl-2 family expression. Mesothelin is a potential target in reducing resistance to cytotoxic drugs.

An integrated study on the role of human papillomaviruses (HPV) in cervical cancer has been conducted. Out of a total of 433 cases of cervical cancer, HPV-DNA was detected in 342 (79%) using the polymerase chain reaction (PCR). The incidence of HPV infection was not significantly related to histological types, although a lower incidence was noted in adenocarcinoma cases. The incidence of lymph node (LN) metastasis in adenosquamous carcinoma (55.6%) was significantly higher than in squamous cell carcinoma (SCC) and adenocarcinoma. HPV 16 was detected significantly more often in SCC than in adenocarcinoma. In contrast, HPV 18 was detected more often in adenocarcinoma than in SCC. As a whole, pelvic LN metastases were found in 24.3% of HPV+ cases, significantly higher than 11% of HPV- cases. However, the significant association of HPV-DNA with LN metastasis was only noted in stage I but not stage II. As far as histological types were concerned, the incidence of positive LN was: HPV+ SCC > HPV- SCC (p < 0.01), whereas HPV- adenocarcinoma > HPV+ adenocarcinoma (p = 0.12). Genotypes of HPV did not have any effect on nodal status. The presence of types of HPV were not associated with tumor size and distribution of clinical stage. Our results suggest that the prognostic significance of HPV-DNA on nodal status is dependent on histological types while the genotypes of HPV cannot account for prognostic significance in cervical cancer.

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