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Tomoyo Okada

Publications and source records attributed to Tomoyo Okada.

5 recordsLinked to original sources
PubMed2026

Targeting eIF4A-dependent translation in genetically complex sarcoma.

Dedifferentiated liposarcoma (DDLS), myxofibrosarcoma (MFS), and undifferentiated pleomorphic sarcoma (UPS) are the most common types of genetically complex sarcoma. There is an urgent need to develop effective targeted therapy for these deadly sarcoma types. Despite their genetic complexity, these sarcomas share genomic alterations causing PI3K/Akt/mTOR and MAPK pathway activation, and both pathways control translation mediated by the RNA helicase eIF4A. We therefore investigated eIF4A inhibition as a therapeutic strategy. The eIF4A inhibitor CR-1-31B effectively suppressed tumor growth and induced apoptosis in DDLS, MFS, and UPS patient-derived cell lines and mouse xenografts. Transcriptome-scale ribosome footprinting identified eIF4A-dependent mRNAs such as the Hippo pathway transcriptional coactivators YAP1 (YAP) and WWTR1 (TAZ). Combined knockdown of YAP and TAZ induced apoptosis in DDLS, MFS, and UPS cell lines, and their ectopic expression partially rescued cells from apoptosis induced by CR-1-31B. Genomic analysis of patient tumors revealed that YAP and WWTR1 were frequently amplified or gained in DDLS, MFS, and UPS and were associated with worse clinical outcomes. Together, our findings identify a strategy for targeting the Hippo pathway in incurable forms of sarcoma based on inhibition of eIF4A-dependent translation of the key oncogenic transcription factors YAP and TAZ.

Humans↗
PubMed2006

Increased expression of connexin 26 in the invasive component of lung squamous cell carcinoma: significant correlation with poor prognosis.

Reduced expression of connexins (Cxs), gap junction proteins, is frequently reported in malignant cell lines and tumors, whereas recent studies suggested that C x 26, a subtype of Cxs, might help tumor cells acquire malignant phenotypes. To examine this suggestion in the clinical setting, 50 lung squamous cell carcinomas (SCCs) were stained with the anti-C x 26 antibody. No C x 26-specific signals were detectable in 34 tumors (group I; 68%), whereas the remaining 16 were judged positive for C x 26 (group II; 32%). In 14 tumors of group II, C x 26-specific signals were detected not in all SCC cells but in SCC cells facing the tumor stroma or capsule, in which the signals were localized on the plasma membrane. Involved lymph nodes of group-II patients often contained metastatic foci consisting of all C x 26-positive cells. The proportion of C x 26-positive to C x 26-negative SCC cells in the metastatic nodes was larger than that in the corresponding primary tumors. C x 26-positive SCC cells seemed to be more invasive and metastatic than negative ones. Consistently, the 5-year cancer-specific survival rate of group-II patients was significantly lower than that of group-I patients (12.5 vs 38.9%; P=0.0391). Multivariate analysis demonstrated that C x 26 expression (P=0.0448) as well as pathological stage (P=0.0338) and vascular invasion (P=0.0191) were independent, significant prognostic predictors. These results suggest that C x 26 may represent an essential effector for controlling the biological aggressiveness of lung SCC tumor.

Biomarkers, Tumor↗
PubMed2005

Merlin/NF-2 mediates contact inhibition of growth by suppressing recruitment of Rac to the plasma membrane.

Introduction of activated p21-activated kinase (PAK) is sufficient to release primary endothelial cells from contact inhibition of growth. Confluent cells display deficient activation of PAK and translocation of Rac to the plasma membrane at matrix adhesions. Targeting Rac to the plasma membrane rescues these cells from contact inhibition. PAK's ability to release human umbilical vein endothelial cells from contact inhibition is blocked by an unphosphorylatable form of its target Merlin, suggesting that PAK promotes mitogenesis by phosphorylating, and thus inactivating, Merlin. Merlin mutants, which are presumed to exert a dominant-negative effect, enable recruitment of Rac to matrix adhesions and promote mitogenesis in confluent cells. Small interference RNA-mediated knockdown of Merlin exerts the same effects. Dominant-negative Rac blocks PAK-mediated release from contact inhibition, implying that PAK functions upstream of Rac in this signaling pathway. These results provide a framework for understanding the tumor suppressor function of Merlin and indicate that Merlin mediates contact inhibition of growth by suppressing recruitment of Rac to matrix adhesions.

Cell Adhesion↗
PubMed2003

Clinical implication and prognostic significance of the tumor suppressor TSLC1 gene detected in adenocarcinoma of the lung.

BACKGROUND: Recently, the TSLC1 (tumor suppressor in lung cancer 1) gene has been identified as a novel tumor suppressor in human nonsmall cell lung carcinoma. To the authors' knowledge, the clinical relevance of TSLC1 gene expression has not been studied using patient data and surgical samples. The current study was designed to evaluate whether the TSLC1 gene can serve as a target for the prognostic determination of patients with pulmonary adenocarcinoma. METHODS: A total of 38 patients who were surgically treated for proven primary lung adenocarcinoma were enrolled in the current study. Surgical specimens were examined for TSLC1 protein expression immunohistochemically and by Western blot analysis. The correlation between levels of TSLC1 expression and pathologic characteristics, as well as prognosis, was investigated. RESULTS: All patients underwent a potentially curative resection of their tumor. TSLC1 antigen expression as evaluated by immunohistochemistry was confirmed by immunoblotting. The expression of TSLC1 protein was found to be inversely correlated with advanced disease stage, lymph node involvement, lymphatic permeation, and vascular invasion. The 4-year overall survival rates of patients with a tumor demonstrating high (> 70% positive cells [n = 14 patients]), intermediate (20-70% positive cells [n = 10 patients]), and low (< 20% positive cells [n = 14 patients]) expression of the TSLC1 antigen were 84%, 28%, and 7%, respectively. In addition, the disease-free survival of patients with a tumor that demonstrated a high percentage of TSLC1 protein-positive cells was reported to be significantly better than that of patients with a tumor that showed a low percentage of TSLC1 protein-positive cells. CONCLUSIONS: The loss or reduction of TSLC1 expression in resected lung adenocarcinoma cases was associated with a poor prognosis, indicating that TSLC1 represents a central effector gene for controlling the biologic aggressiveness of the tumor and that it is an essential biomarker for predicting patient prognosis. These data may help to detect those patients at high risk for recurrence who might benefit from additional therapeutic strategies such as adjuvant therapy.

Adenocarcinoma↗