Chi Zhang

β-catenin is a Potential Prognostic Biomarker in Uterine Sarcoma

Introduction Uterine sarcoma (US) is an extremely rare and aggressive gynecologic malignancy with a poor overall survival (OS). The efficient prognostic biomarker is currently lacking. Methods Utilizing a Sweden microarray dataset from the Gene Expression Omnibus (GEO) (GSE119043, n = 50) and a clinical cohort (n = 31) retrospectively collected from Suining Central Hospital, we analyzed β-catenin expression profiles and corresponding clinicopathological characteristics. Immunohistochemistry (IHC) was used to assess β-catenin expression level. Survival analysis was used to assess the relationship between β-catenin expression and prognosis. Gene set enrichment analysis (GSEA) was performed to characterize the specific pathways involved in β-catenin expression. Results Immunohistochemistry indicated that β-catenin expression was significantly upregulated in US group compared to both the normal uterine smooth muscle (UNSM) and uterine leiomyoma (ULM) groups ( P  < .01). IHC also exhibited a significant difference in β-catenin expression levels in four pathological subtypes. Leiomyosarcoma (LMS) and high-grade endometrial stromal sarcoma (HG-ESS) suggested higher levels of β-catenin expression compared with adenosarcoma (AS) or low-grade endometrial stromal sarcoma (LG-ESS), but no statistically significant difference was found in box plot ( P  > .05). GSEA indicated that transcriptional dysregulation in cancer, Wnt, AMPK, MAPK, PI3K, p53, Ras, and TNF signaling pathway were positively enriched in β-catenin high-expression group. Though survival analysis showed that β-catenin expression level was not associated with survival, low-β-catenin expression group showed a longer median OS compared to high expression group (56.17 months VS 9.60 months) in Sweden microarray dataset. Similar results were also observed for progression-free survival (PFS) in clinical cohort (not reached VS 45.97 months in high-expression group). Tumor type, lymphadenectomy, family history of malignancy and tumor recurrence remained significant predictors of OS, while only tumor type, stage and tumor recurrence had prognostic significance for PFS. Age, tumor size, menopausal status, CA125, adjuvant chemotherapy, and adjuvant radiotherapy, were not associated with survival ( P  > .05). Conclusion β-catenin was highly expressed in uterine sarcoma and may be promising as a novel potential biomarker for diagnosis and prognosis.

Orosomucoid 1 is a Potential Prognostic Biomarker for Uterine Sarcoma

Introduction Uterine sarcoma (US) is a rare tumor characterized by high aggressiveness, a tendency for recurrence and distant metastasis, and an extremely poor prognosis. In this study, we evaluated the expression of Orosomucoid 1 (ORM1) in different subtypes of US and the relationship between survival rates and clinicopathological features. Method A retrospective study was conducted on 50 cases diagnosed with US in our hospital from 2011 to 2023. Immunohistochemistry (IHC) was used to detect the expression levels of ORM1 in different subtypes of US.The chi-square test and Kaplan-Meier survival analysis were used to analyze the relationship between ORM1 expression and clinical parameters as well as prognosis. Cox analysis was employed to evaluate the relationships between prognosis and clinical parameters in US. Result Compared to normal proliferative endometrial tissue (NPE), the expression of ORM1 was downregulated in low-grade endometrial stromal sarcoma (LG-ESS), high-grade endometrial stromal sarcoma (HG-ESS), and undifferentiated uterine sarcoma (UUS) (P < .001,P < .001,and P < .001, respectively). Compared to normal uterine smooth muscle tissue (UNSM), the expression of ORM1 was upregulated in leiomyosarcoma (LMS) (P = .006). High ORM1 expression levels in US patients were associated with poor overall survival (OS) and progression-free survival (PFS) (P = .027 and P = .005, respectively). Multivariate COX analysis revealed that tumor stage and ORM1 expression are independent prognostic factors for US patients. Conclusion ORM1 is expressed at low levels in ESS and at high levels in LMS. ORM1 potentially serve as a novel biomarker for the diagnosis, classification, and prognosis of US.

Deubiquitinase UCHL1 Maintains Protein Homeostasis through the PSMA7–APEH–Proteasome Axis in High-grade Serous Ovarian Carcinoma

Abstract High-grade serous ovarian cancer (HGSOC) is characterized by chromosomal instability, DNA damage, oxidative stress, and high metabolic demand that exacerbate misfolded, unfolded, and damaged protein burden resulting in increased proteotoxicity. However, the underlying mechanisms that maintain protein homeostasis to promote HGSOC growth remain poorly understood. This study reports that the neuronal deubiquitinating enzyme, ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), is overexpressed in HGSOC and maintains protein homeostasis. UCHL1 expression was markedly increased in HGSOC patient tumors and serous tubal intraepithelial carcinoma (HGSOC precursor lesions). High UCHL1 levels correlated with higher tumor grade and poor patient survival. UCHL1 inhibition reduced HGSOC cell proliferation and invasion, as well as significantly decreased the in vivo metastatic growth of ovarian cancer xenografts. Transcriptional profiling of UCHL1-silenced HGSOC cells revealed downregulation of genes implicated with proteasome activity along with upregulation of endoplasmic reticulum stress–induced genes. Reduced expression of proteasome subunit alpha 7 (PSMA7) and acylaminoacyl peptide hydrolase (APEH), upon silencing of UCHL1, resulted in a significant decrease in proteasome activity, impaired protein degradation, and abrogated HGSOC growth. Furthermore, the accumulation of polyubiquitinated proteins in the UCHL1-silenced cells led to attenuation of mTORC1 activity and protein synthesis, and induction of terminal unfolded protein response. Collectively, these results indicate that UCHL1 promotes HGSOC growth by mediating protein homeostasis through the PSMA7–APEH–proteasome axis. Implications: This study identifies the novel links in the proteostasis network to target protein homeostasis in HGSOC and recognizes the potential of inhibiting UCHL1 and APEH to sensitize cancer cells to proteotoxic stress in solid tumors.