Shie Wang

Trps1 predicts poor prognosis in advanced high grade serous ovarian carcinoma

AbstractTRPS1 is aberrantly expressed in a variety of tumors, including breast, prostate, and gastric cancers, and is strongly associated with tumorigenesis or prognosis. However, the role of TRPS1 in high grade serous ovarian carcinoma (HGSC) is unknown. We investigated the relationship between TRPS1 expression and clinicopathology in HGSC patients. The tumor‐related regulatory mechanisms of TRPS1 was explored through in vivo and vitro experiments. The results showed that TRPS1 was highly expressed in HGSC compared to normal tissues. It was also linked to the cell proliferation index Ki67 and poor prognosis. In vivo experiments showed that knockdown of TRPS1 could inhibit tumor growth. In vitro experiments, knockdown of TRPS1 inhibited the proliferation of ovarian cancer cells. TRPS1 exerted its regulatory role as a transcription factor, binding to the PSAT1 promoter and promoting the expression of PSAT1 gene. Meanwhile, PSAT1 was positively correlated with CCND1 expression. These results suggest that TRPS1 affects HGSC proliferation and cell cycle by regulating PSAT1 and thus CCND1 expression.

EIF1AX Nucleolar Condensates Enhance Susceptibilities for the Management of Endometrial Cancer

Abstract Endometrial cancer harboring TP53 aberrations presents a significant therapeutic challenge due to the lack of druggable targets. A promising strategy involves inducing senescence in cancer cells followed by targeted elimination using senolytic agents. The preliminary findings indicated that the aberrant subcellular localization of EIF1AX in endometrial cancer is significantly correlated with a poor prognosis. In this study, a compound library is employed to screen for therapeutic agents that induce the nuclear localization of EIF1AX in endometrial cancer cells, followed by a CRISPR library screen to identify senolytic compounds. The results demonstrated that the combination of 2,5‐MeC and dacinostat effectively inhibited tumor growth. Mechanistically, co‐immunoprecipitation mass spectrometry and cleavage under targets and tagmentation sequencing analyses demonstrated that 2,5‐MeC acts as a potent inducer of EIF1AX nucleolar translocation. This translocation promoted senescence by recruiting DDX21 to form nucleolar aggregates, which suppressed rDNA transcription. Additionally, RNA sequencing and antibody array analyses revealed that the synthetic lethality of 2,5‐MeC and dacinostat is mediated through the activation of the JNK/MAPK signaling pathway. Collectively, these findings highlight a novel therapeutic strategy for TP53‐aberrant endometrial cancer.

XPO1‐Mediated EIF1AX Cytoplasmic Relocation Promotes Tumor Migration and Invasion in Endometrial Carcinoma

Dysregulation of eukaryotic translation initiation factor 1A, X‐linked (EIF1AX), has been implicated in the pathogenesis of some cancers. However, the role of EIF1AX in endometrial carcinoma (EC) remains unknown. We investigated the EIF1AX expression in EC patients and assessed its tumorigenesis‐associated function and nucleocytoplasmic transport mechanism in vitro and in vivo. The results indicated that the cytoplasmic EIF1AX expression showed a gradual increase when going from endometrium normal tissue, simple endometrial hyperplasia, complex endometrial hyperplasia, and endometrial atypical hyperplasia to EC, while vice versa for the nuclear EIF1AX expression. In addition, the cytoplasmic EIF1AX expression was positively correlated with histologic type, high International Federation of Gynecology and Obstetrics (FIGO) grade, advanced FIGO stage, deeper infiltration, high Ki67 index, and shorter recurrence‐free survival in EC patients. In vitro, short hairpin RNA‐mediated EIF1AX depletion or SV40NLS‐mediated EIF1AX import into the nucleus in multiple human EC cells potently suppressed cell migration and invasion, epithelial‐mesenchymal transition, and lung metastasis. Moreover, exportin 1 induced the transport of EIF1AX from the nucleus to the cytoplasm that could be inhibited by leptomycin B treatment or the mutation in the EIF1AX location sequence. These results demonstrate that cytoplasmic EIF1AX may play a key role in the incidence and promotion of EC, and thus, targeting EIF1AX or its nucleocytoplasmic transport process may offer an effective new therapeutic approach to EC.

Long noncoding RNA EIF1AX‐AS1 promotes endometrial cancer cell apoptosis by affecting EIF1AX mRNA stabilization

AbstractLong noncoding RNAs (lncRNAs) have been found to play an important role in the occurrence and development of endometrial carcinoma (EC). Here, using RNA sequencing analysis, we systemically screened and identified the lncRNA eukaryotic translation initiation factor 1A, X‐linked (EIF1AX)‐AS1, which is aberrantly downregulated in clinical EC tissues and closely correlated with tumor type. EIF1AX‐AS1 markedly inhibited EC cell proliferation and promoted apoptosis in vitro and in vivo. Mechanistically, EIF1AX‐AS1 interacts with EIF1AX mRNA and poly C binding protein 1 (PCBP1), which promote EIF1AX mRNA degradation. Intriguingly, by interacting with internal ribosome entry site‐related protein Y‐box binding protein 1 (YBX‐1), EIF1AX promotes c‐Myc translation through the internal ribosome entry site pathway. c‐Myc promotes EIF1AX transcription and thus forms a feed‐forward loop to regulate EC cell proliferation. Taken together, these data reveal new insights into the biology driving EC proliferation and highlights the potential of lncRNAs as biomarkers for prognosis and future therapeutic targets for cancer.

Juvenile Granulosa Cell Tumors of the Ovary

Abstract Objective To explore the clinical and pathologic features of ovarian juvenile granulosa cell tumors (JGCTs). Methods Clinical data, histopathologic observations, immunohistochemical results, FOXL2 mutation status, and follow-up information of 7 JGCT cases were studied. Results The patients most commonly presented with abdominal distension and pain (5 cases), followed by precocious puberty (1 case) and a pelvic mass (1 case). Six patients had stage I disease, and 1 had stage IV disease. The microscopic examinations typically showed lobular growth punctuated by variably sized and shaped follicles. Rare features included a reticular-cystic appearance mimicking a yolk sac tumor (2 cases), a lobular appearance similar to a sclerosing stromal tumor (1 case), strands and cords (1 case), pseudopapillary appearance (2 cases), spindle cell appearance (1 case), microcystic appearance (1 case), hobnail cells (1 case), and rhabdomyoid cells (1 case). No FOXL2 mutation was encountered. After a median follow-up of 53 months, only 1 patient with a strongly diffuse TP53-positive tumor died of the disease, and 2 successfully had babies. Conclusions JGCT is a rare neoplasm with a wide morphologic spectrum and is easily confused with other tumors. Familiarity with the characteristics, rare atypical appearances, and immunohistochemical results may aid in obtaining a correct diagnosis.