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Stat3 activation in human endometrial and cervical cancers.

ABSTRACT: The activation of signal transducer and activator of transcription 3 (Stat3) has been implicated in the oncogenesis of cancer and is regarded as a novel target for cancer therapy. Stat3 is classified as a proto-oncogene, because an activated form of Stat3 can mediate oncogenic transformation in cultured cells and tumour formation in nude mice. The constitutive activation of Stat3 has been frequently detected in various types of human cancers. However, the constitutive activation of Stat3 in endometrial and cervical cancers has not been studied. We examined tyrosine phosphorylation of Stat3 (activated form of Stat3) in multiple endometrial and cervical cancer tissues using tissue microarray slides as well as cancer cell lines to explore the possible activation of Stat3. Our results indicated that elevated phosphorylation of Stat3 was detected in cervical and endometrial cancer cell lines. Our results also showed that elevated levels of phosphorylation of Stat3 protein were detected in the endometrial and cervical cancer specimens. This is the first study to demonstrate that Stat3 is activated in human endometrial and cervical cancer tissues. Immunohistochemical staining showed that activated Stat3 is associated with increased expression of downstream antiapoptotic genes, Bcl-xL, survivin, and Mcl-1 in these tissues. Expression of a dominant-negative Stat3 mutant using adenovirus-mediated gene transfer inhibited cell growth and induced apoptosis in HeLa and SiHa cervical cancer cell lines expressing elevated levels of Stat3 phosphorylation. Further, a JAK/Stat3 small molecular inhibitor, JSI-124, induced apoptosis more selectively in HeLa and SiHa cancer cell lines than Ishikawa cell line without elevated levels of Stat3 phosphorylation. These results indicate that Stat3 is activated in human endometrial and cervical cancers and the inhibition of constitutive Stat3 signaling may be an effective target for cancer intervention in these two cancers.

SUBMITTER: Chen CL

PROVIDER: S-EPMC2360038 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Increasingly, the matrisome, a set of proteins that form the core of the extracellular matrix (ECM) or are closely associated with it, has been demonstrated to play a key role in tumor progression. However, in the context of gynecological cancers, the matrisome has not been well characterized. A holistic, yet targeted, exploration of the tumor microenvironment is critical for better understanding the progression of gynecological cancers, identifying key biomarkers for cancer progression, establishing the role of gene expression in patient survival, and for assisting in the development of new targeted therapies. In this work, we explored the matrisome gene expression profiles of cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), uterine corpus endometrial carcinoma (UCEC), and uterine carcinosarcoma (UCS) using publicly available RNA-seq data from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) portal. We hypothesized that the matrisomal expression patterns of CESC, UCEC, and UCS would be highly distinct with respect to genes which are differentially expressed and hold inferential significance with respect to tumor progression, patient survival, or both. Through a combination of statistical and machine learning analysis techniques, we identified sets of genes and gene networks which characterized each of the gynecological cancer cohorts. Our findings demonstrate that the matrisome is critical for characterizing gynecological cancers and transcriptomic mechanisms of cancer progression and outcome. Furthermore, while the goal of pan-cancer transcriptional analyses is often to highlight the shared attributes of these cancer types, we demonstrate that they are highly distinct diseases which require separate analysis, modeling, and treatment approaches. In future studies, matrisome genes and gene ontology terms that were identified as holding inferential significance for cancer stage and patient survival can be evaluated as potential drug targets and incorporated into in vitro models of disease.

Project description:BACKGROUND:Since intensity-modulated radiation therapy (IMRT) has become popular for the treatment of gynecologic cancers, the contouring process has become more critical. This study evaluated the feasibility of atlas-based auto-segmentation (ABAS) for contouring in patients with endometrial and cervical cancers. METHODS:A total of 75 sets of planning CT images from 75 patients were collected. Contours for the pelvic nodal clinical target volume (CTV), femur, and bladder were carefully generated by two skilled radiation oncologists. Of 75 patients, 60 were randomly registered in three different atlas libraries for ABAS in groups of 20, 40, or 60. ABAS was conducted in 15 patients, followed by manual correction (ABASc). The time required to generate all contours was recorded, and the accuracy of segmentation was assessed using Dice's coefficient (DC) and the Hausdorff distance (HD) and compared to those of manually delineated contours. RESULTS:For ABAS-CTV, the best results were achieved with groups of 60 patients (DC, 0.79; HD, 19.7?mm) and the worst results with groups of 20 patients (DC, 0.75; p?=?0.012; HD, 21.3?mm; p?=?0.002). ABASc-CTV performed better than ABAS-CTV in terms of both HD and DC (ABASc [n?=?60]; DC, 0.84; HD, 15.6?mm; all p?<?0.017). ABAS required an average of 45.1?s, whereas ABASc required 191.1?s; both methods required less time than the manual methods (p?<?0.001). Both ABAS-Femur and simultaneous ABAS-Bilateral-femurs showed satisfactory performance, regardless of the atlas library used (DC >?0.9 and HD ?10.0?mm), with significant time reduction compared to that needed for manual delineation (p?<?0.001). However, ABAS-Bladder did not prove to be feasible, with inferior results regardless of library size (DC?<?0.6 and HD?>?40?mm). Furthermore, ABASc-Bladder required a longer processing time than manual contouring to achieve the same accuracy. CONCLUSIONS:ABAS could help physicians to delineate the CTV and organs-at-risk (e.g., femurs) in IMRT planning considering its consistency, efficacy, and accuracy.

Project description:BACKGROUND: Recent observations indicate potential role of transcription factor STAT3 in cervical cancer development but its role specifically with respect to HPV infection is not known. Present study has been designed to investigate expression and activation of STAT3 in cervical precancer and cancer in relation to HPV infection during cervical carcinogenesis. Established cervical cancer cell lines and prospectively-collected cervical precancer and cancer tissues were analyzed for the HPV positivity and evaluated for STAT3 expression and its phosphorylation by immunoblotting and immunohistochemistry whereas STAT3-specific DNA binding activity was examined by gel-shift assays. RESULTS: Analysis of 120 tissues from cervical precancer and cancer lesions or from normal cervix revealed differentially high levels of constitutively active STAT3 in cervical precancer and cancer lesions, whereas it was absent in normal controls. Similarly, a high level of constitutively active STAT3 expression was observed in HPV-positive cervical cancer cell lines when compared to that of HPV-negative cells. Expression and activity of STAT3 were found to change as a function of severity of cervical lesions from precancer to cancer. Expression of active pSTAT3 was specifically high in cervical precancer and cancer lesions found positive for HPV16. Interestingly, site-specific accumulation of STAT3 was observed in basal and suprabasal layers of HPV16-positive early precancer lesions which is indicative of possible involvement of STAT3 in establishment of HPV infection. In HPV16-positive cases, STAT3 expression and activity were distinctively higher in poorly-differentiated lesions with advanced histopathological grades. CONCLUSION: We demonstrate that in the presence of HPV16, STAT3 is aberrantly-expressed and constitutively-activated in cervical cancer which increases as the lesion progresses thus indicating its potential role in progression of HPV16-mediated cervical carcinogenesis.

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Stat3 activation in human endometrial and cervical cancers.

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