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The rising mortality rate from cancer, driven by the absence of reliable biomarkers, highlights the pressing need for advanced diagnostic and prognostic strategies. This study investigates LZTS2’s role as a pan-cancer biomarker, emphasizing its predictive value for immunotherapy and therapeutic targeting. Unlike existing biomarkers such as AFP in hepatocellular carcinoma or HER2 in gastric cancer, which exhibit tissue-specific utility, LZTS2 demonstrates unique cross-cancer applicability, as evidenced by its consistent dysregulation in both liver hepatocellular carcinoma (LIHC) and stomach adenocarcinoma (STAD) alongside emerging associations with other malignancies. Leveraging advanced bioinformatics tools and databases including UALCAN, KM-plotter, and The Cancer Genome Atlas (TCGA), alongside experimental validation in LIHC and STAD cell lines, we analyze LZTS2 expression patterns and their clinical relevance. Notably, LZTS2’s dual role—acting as a tumor suppressor in some cancers while promoting oncogenesis in others—distinguishes it from conventional single-function markers, offering novel insights into its regulatory versatility. Our findings reveal that LZTS2 mutations and expression levels are closely associated with cancer progression and patient survival, solidifying its potential as a prognostic biomarker. Notably, LZTS2 expression correlates with various clinicopathological parameters, underscoring its significance in cancer biology. Pathway analysis highlights LZTS2’s involvement in critical biological processes, providing actionable insights for therapeutic interventions. Quantitative real-time polymerase chain reaction (qRT-PCR) and quantitative methylation-specific PCR (qMSP) experimental validations confirm these results, further establishing LZTS2’s utility as a multi-dimensional biomarker that integrates genetic, epigenetic, and immunological features—a capability rarely observed in existing markers. This comprehensive analysis positions LZTS2 as a pivotal player in cancer progression, opening promising avenues for enhanced clinical management.

Background Despite significant advancements in therapeutic approaches for lung cancer, the prognosis of lung squamous cell carcinoma (LUSC) remains suboptimal, underscoring the critical need to identify novel molecular targets and develop targeted therapeutic strategies. Through bioinformatic analysis, SH3RF2 was identified as a gene significantly upregulated in LUSC patients, and its high expression was strongly associated with lower survival rates. However, no significant differences in expression or survival correlation were observed in lung adenocarcinoma. Notably, SH3RF2, an E3 ubiquitin ligase characterized by three SH3 domains, has not been systematically investigated in LUSC pathogenesis. Results Mechanistic investigations found that SH3RF2 promoted tumor cell proliferation, upregulated M2 markers (Arg-1, CD163, IL-10), increased CD206 + subpopulation of M0 THP-1 cells and enhanced migration and invasion of M0 THP-1 cells. SH3RF2 promoted the nuclear translocation of β-catenin. Furthermore, ICG-001, the inhibitors of β-catenin pathway, alleviated the above effects of SH3RF2. In vivo tumorigenesis experiments found that SH3RF2 promoted tumor growth and increased the proportion of M2 cells. Proteomic analysis revealed that SH3RF2 interacted with LZTS2 and regulated the ubiquitination of LZTS2 with RING domain. Overexpression of LZTS2 attenuated SH3RF2-induced nuclear translocation of β-catenin, suppressed cellular migration and invasion, and inhibited M2 polarization promoted by SH3RF2 overexpression. The combination of SH3RF2 knockdown and radiotherapy inhibited the growth of tumor compared with SH3RF2 knockdown or radiotherapy alone. Conclusions This study demonstrates the functionality of SH3RF2 in both potentiating tumor progression and inducing M2 macrophage polarization through coordinated regulation of LZTS2 degradation and β-catenin nuclear translocation. These findings establish a novel mechanistic framework and propose SH3RF2-associated signaling axes as promising therapeutic targets for LUSC.

MicroRNAs (miRNAs) are small noncoding RNAs that have been critically implicated in several human cancers. miRNAs are thought to participate in various biological processes, including proliferation, cell cycle, apoptosis, and even the regulation of the stemness properties of cancer stem cells. In this study, we explore the potential role of miR-300 in glioma stem-like cells (GSLCs). We isolated GSLCs from glioma biopsy specimens and identified the stemness properties of the cells through neurosphere formation assays, multilineage differentiation ability analysis, and immunofluorescence analysis of glioma stem cell markers. We found that miR-300 is commonly upregulated in glioma tissues, and the expression of miR-300 was higher in GSLCs. The results of functional experiments demonstrated that miR-300 can enhance the self-renewal of GSLCs and reduce differentiation toward both astrocyte and neural fates. In addition, LZTS2 is a direct target of miR-300. In conclusion, our results demonstrate the critical role of miR-300 in GSLCs and its functions in LZTS2 inhibition and describe a new approach for the molecular regulation of tumor stem cells.

β-catenin is a component of the adhesion complex linking cadherin and actin cytoskeleton, as well as a major mediator of the Wnt pathway, which is a critical signal cascade regulating embryonic development, cell polarity, carcinogenesis, and stem cell function. NF-κB functions as a key regulator of immune responses and apoptosis, and mutations in NF-κB signaling can lead to immune diseases and cancers. We previously showed that NF-κB-mediated modulation of β-catenin/Tcf signaling is mediated by leucine zipper tumor suppressor 2 (Lzts2) and that lzts2 expression is differentially regulated in various cancer cells. Its functional significances, however, are poorly understood. We showed that NF-κB-induced modulation of β-catenin/Tcf pathway is regulated by lzts2 expression in mesenchymal stem cells (MSCs) and several cancer cells, and that NF-κB-induced lzts2 expression is differentially regulated among cancer cell types. Here, using a promoter–reporter assay and EMSA, we demonstrate that NF-κB regulates lzts2 transcription by directly binding to the lzts2 promoter, and that NF-κB-induced lzts2 transcription differs by cell types. Modulation of lzts2 expression by lentiviral techniques affected proliferation and tumorigenicity of several cancer cell lines such as breast, colon, prostate cancer, and glioma, but did not affect cisplatin sensitivity or cell migration. Our data indicate that lzts2 expression is transcriptionally regulated by NF-κB activities, and the modulation of lzts2 expression affects cell proliferation and tumor growth through the Wnt/β-catenin pathway in various cancer cell lines.