It is suggested that TP53AIP1 may serve as a potential prognostic biomarker and tumor-suppressive candidate in breast cancer, with its effects at least partly associated with MAPK pathway attenuation.
Abstract
Tumor protein p53-regulated apoptosis-inducing protein 1 (TP53AIP1) has been implicated in tumor suppression, but its role in breast cancer remains unclear. This study evaluated the expression pattern, prognostic value, immune infiltration association, methylation status, and biological function of TP53AIP1 in breast cancer using TCGA transcriptomic data, public methylation datasets, immunohistochemistry, and in vitro experiments. TP53AIP1 was significantly downregulated in breast cancer tissues and was identified as an independent prognostic factor for poor survival. TP53AIP1 expression was positively associated with transcriptome-estimated infiltration of natural killer cells, mast cells, and plasmacytoid dendritic cells. Methylation analysis showed that TP53AIP1 promoter hypermethylation was associated with reduced TP53AIP1 expression, suggesting a potential epigenetic silencing mechanism. Functionally, TP53AIP1 overexpression suppressed breast cancer cell proliferation, migration, invasion, and epithelial-mesenchymal transition and, promoted apoptosis and cell-cycle arrest. Mechanistically, TP53AIP1 overexpression reduced MEK/ERK phosphorylation, whereas MAPK pathway reactivation partially reversed its inhibitory effects on malignant phenotypes. These findings suggest that TP53AIP1 may serve as a potential prognostic biomarker and tumor-suppressive candidate in breast cancer, with its effects at least partly associated with MAPK pathway attenuation.
Elevated TPD52 expression was associated with longer overall survival in specific subgroups, including the basal-like subtype, invasive lobular carcinoma, and N0/N1 stages, and a random forest-based diagnostic model demonstrated high accuracy across multiple datasets.
J. Yu, Z. Zhu, R. Deng et al.· medRxiv· 0 citations
GPR19 functions as a novel oncogenic driver and clinically relevant biomarker in breast cancer, particularly in TP53-mutant and TNBC subsets, and was significantly upregulated in TP53-mutant breast cancer, primary tumors, and especially TNBC.
Jihan Qiu, Cheng Tian, Hanzhi Li et al.· Frontiers in Bioscience· 0 citations
Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide, with limited biomarkers available for early diagnosis and targeted therapy. AKR1B15, a lesser-studied member of the aldo-keto reductase family, shares high sequence similarity with AKR1B10, but its role in HCC remains unclear. Therefore, this study aimed to investigate the biological function of AKR1B15 in HCC and its involvement in oncogenic signaling pathways. Bioinformatic analysis of gene expression datasets and patient tissue samples was used to evaluate AKR1B15 expression and prognostic relevance. Functional assays were conducted following AKR1B15 knockdown, including CCK-8, colony formation, transwell, wound healing, flow cytometry, and xenograft models. Western blotting and immunofluorescence were employed to assess phosphorylation of key signaling molecules. AKR1B15 expression was significantly elevated in HCC tissues and associated with higher pathologic T stage and worse disease-specific survival (P < 0.05). AKR1B15 knockdown inhibited HCC cell proliferation, invasion, and migration (P < 0.01), and promoted apoptosis (P < 0.001). In vivo, AKR1B15 depletion suppressed tumor growth and reduced Ki-67 expression. Mechanistically, silencing AKR1B15 decreased phosphorylation of p53 (Ser15), PI3K (Tyr458/199), AKT (Ser473), mTOR (Ser2448), and E2F1 (S364), indicating inhibition of the p53-PI3K-AKT-mTOR-E2F1 axis. AKR1B15 promotes HCC progression and is associated with activation of the p53-PI3K-AKT-mTOR-E2F1 signaling pathway. It may serve as a novel diagnostic marker and therapeutic target in hepatocellular carcinoma.
Jie Li, Wei-lai Chen, Pin-Ting Wu et al.· Scientific Reports· 0 citations
Introduction Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by limited targeted therapeutic options and frequent activation of the PI3K/AKT signaling pathway. EI24, a p53-responsive tumor suppressor involved in apoptosis, autophagy, and oncogenic signaling regulation, has been implicated in multiple cancer types; however, its functional role and molecular mechanism in TNBC remain incompletely understood. This study investigated the clinical relevance of EI24 in TNBC and examined its impact on AKT signaling and tumor progression. Methods Public breast cancer datasets and breast cancer patient samples were analyzed to assess EI24 expression patterns and clinical associations. Doxycycline-inducible EI24 overexpression systems were established in TNBC cell lines to evaluate cell proliferation and AKT pathway activity. Human phospho-kinase arrays, immunoblotting, co-immunoprecipitation, domain-mapping analyses, and immunofluorescence assays were performed to investigate the molecular mechanism underlying EI24-mediated AKT regulation. In vivo functional effects were examined using the MMTV-PyMT mammary tumor mouse model combined with mammary gland-specific Ei24 overexpression. Results EI24 expression was significantly reduced in TNBC patient samples and lower EI24 expression was associated with advanced tumor progression and poorer relapse-free survival. Inducible EI24 overexpression suppressed proliferation of TNBC cell lines and reduced AKT phosphorylation at both S473 and T308. In the MMTV-PyMT model, Ei24 overexpression inhibited mammary tumor growth, reduced pulmonary metastasis, and prolonged survival. Mechanistically, EI24 interacted with the pleckstrin-homology (PH) domain of AKT and impaired growth factor-induced AKT membrane translocation, suggesting that EI24 negatively regulates AKT activation by interfering with its spatial recruitment to the plasma membrane. Discussion These findings identify EI24 as a negative regulator of AKT signaling and support its tumor-suppressive role in TNBC progression. Our study provides mechanistic and in vivo evidence linking EI24 to AKT pathway regulation and supports further investigation of EI24-based approaches as potential therapeutic strategies for AKT-driven TNBC.
T. Nam, You Min Kim, Hye Mi Park et al.· Frontiers in Oncology· 0 citations
Breast cancer remains a primary cause of cancer-associated death globally, largely due to distant metastasis and therapeutic resistance. While matrix remodeling associated 5 (MXRA5) has been implicated in inflammation and fibrosis, its specific biological function and mechanistic role in breast cancer progression remain unclear. Herein, multi-omics analysis and in vitro functional assays were employed to investigate the expression pattern, clinical significance, and biological function of MXRA5 within breast cancer. We observed that MXRA5 was considerably upregulated within breast cancer tissues in comparison with normal controls at both mRNA and protein levels. Crucially, elevated MXRA5 expression exhibited a positive correlation with advanced lymph node metastasis and impaired clinical prognosis, including overall survival, disease-specific survival, and progression-free interval, particularly within the Luminal B and HER2+ subtypes. Functional validation demonstrated that MXRA5 silencing markedly repressed the abilities of BT474 and MDA-MB-361 cells to proliferate, to migrate, and to invade in vitro, and significantly reduced lung metastasis in vivo. Mechanistically, bioinformatics analysis and pharmacological rescue experiments demonstrated that MXRA5 promotes tumor aggressiveness by activating the PI3K/AKT/mTOR signaling axis, which subsequently drives the epithelial-to-mesenchymal transition (EMT) pathway, evidenced by the positive regulation of key EMT transcription factors Snail and Twist, as well as the mesenchymal marker Vimentin. Collectively, these findings identify MXRA5 as a novel oncogenic driver in breast carcinoma and reveal its potential as a valuable prognostic biomarker and therapeutic target for managing metastatic disease.
Jian Wang, Jie Tang, Yaoxin Wang· Korean Journal of Physiology...· 0 citations
Results provide experimental support for targeting the PI3K/AKT/mTOR axis as a potential therapeutic strategy in cervical cancer through functional and mechanistic link between recurrent PIK3CA-E545K-MUT and aggressive tumor behavior in cervical cancer via AKT/mTOR pathway activation.
Congxiu Huang, Wei Zhang, Xiaoyu Ma et al.· Zeitschrift für Induktive Ab...· 0 citations
