Elucidating the roles of ASPM isoforms reveals a novel prognostic marker for pancreatic cancer

Timaner, Michael; Shaked, Yuval

doi:10.1002/path.5355

Cited by 12 publications

(9 citation statements)

References 12 publications

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“…Whilst the preceding data support the importance of ASPM in GC, they did not distinguish among different protein isoforms of ASPM, which may play different roles in oncogenesis [20,36]. To this end, we carried out TMA analysis of 59 GC tissues and the paired normal gastric epithelium for the staining of ASPMiI and ASPMiII using isoform-specific antibodies recently developed by our group.…”

Section: The Expression Of Aspmii Is Prognostically Important In Gcmentioning

confidence: 96%

A multi-mode Wnt- and stemness-regulatory module dictated by FOXM1 and ASPM isoform I in gastric cancer

et al. 2021

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Background Gastric cancer (GC) is the third leading cause of cancer mortality globally and a molecularly heterogeneous disease. Identifying the driver pathways in GC progression is crucial to improving the clinical outcome. Recent studies identified ASPM (abnormal spindle-like microcephaly-associated) and FOXM1 (Forkhead box protein M1) as novel Wnt and cancer stem cell (CSC) regulators; their pathogenetic roles and potential crosstalks in GC remain unclarified. Methods The expression patterns of ASPM isoforms and FOXM1 were profiled in normal gastric epithelial and GC tissues. The functional roles of ASPM and FOXM1 in Wnt activity, cancer stemness and GC progression, and the underlying signaling processes were investigated. Results Approximately one third of GC cells upregulate the expression of ASPM isoform I (ASPMiI) in their cytoplasm; the tumors with a high ASPMiI positive score (≥ 10%) are associated with a poor prognosis of the patients. Mechanistically, the molecular interplay among FOXM1, ASPMiI and DVL3 was found to converge on β-catenin to control the Wnt activity and the stemness property of GC cells. This multi-mode Wnt-regulatory module serves to reinforce Wnt signals in CSCs by transcriptional regulation (FOXM1-ASPM), protein-protein interactions (ASPMiI-DVL3-β-catenin), and nuclear translocation (FOXM1-β-catenin). Conclusions This study illuminates a novel Wnt-and stemness-regulatory mechanism in GC cells and identifies a novel subset of FOXM1 high ASPMiI high GC with potential to guide Wnt-and stemness-related diagnostics and therapies.

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Section: The Expression Of Aspmii Is Prognostically Important In Gcmentioning

confidence: 96%

A multi-mode Wnt- and stemness-regulatory module dictated by FOXM1 and ASPM isoform I in gastric cancer

et al. 2021

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“…Previous studies have shown that ASPM is highly expressed in a variety of cancers and is related to a poor clinical prognosis and recurrence ( 37 ). Accumulating evidence suggests that ASPM is a regulator of cell stemness, it enhances stem cell phenotype in prostate cancer cells by enhancing Wnt/β-catenin signaling, thereby promoting tumor aggressiveness ( 38 ). ASPM acts as an immune-related gene in bladder cancer ( 23 ).…”

Section: Discussionmentioning

confidence: 99%

ASPM Is a Prognostic Biomarker and Correlates With Immune Infiltration in Kidney Renal Clear Cell Carcinoma and Liver Hepatocellular Carcinoma

Deng

Liu

et al. 2022

Front. Oncol.

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BackgroundAbnormal spindle microtubule assembly (ASPM) is a centrosomal protein and that is related to a poor clinical prognosis and recurrence. However, the relationship between ASPM expression, tumor immunity, and the prognosis of different cancers remains unclear.MethodsASPM expression and its influence on tumor prognosis were analyzed using the Tumor Immune Estimation Resource (TIMER), UALCAN, OncoLnc, and Gene Expression Profiling Interactive Analysis (GEPIA) databases. The relationship between ASPM expression and tumor immunity was analyzed using the TIMER and GEPIA databases, and the results were further verified using qPCR, western blot, and multiplex quantitative immuno fluorescence.ResultsThe results showed that ASPM expression was significantly higher in most cancer tissues than in corresponding normal tissues, including kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), pancreatic adenocarcinoma (PAAD), and breast invasive carcinoma (BRCA). ASPM expression was significantly higher in late-stage cancers than in early-stages cancers (e.g., KIRC, KIRP, LIHC, LUAD, and BRCA; p < 0.05), demonstrating a possible role of ASPM in cancer progression and invasion. Moreover, our data showed that high ASPM expression was associated with poor overall survival, and disease-specific survival in KIRC and LIHC (p < 0.05). Besides, Cox hazard regression analysis results showed that ASPM may be an independent prognostic factor for KIRC and LIHC. ASPM expression showed a strong correlation with tumor-infiltrating B cells, CD8+ T cells, and M2 macrophages in KIRC and LIHC.ConclusionsThese findings demonstrate that the high expression of ASPM indicates poor prognosis as well as increased levels of immune cell infiltration in KIRC and LIHC. ASPM expression may serve as a novel prognostic biomarker for both the clinical outcome and immune cell infiltration in KIRC and LIHC.

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“…An improper response to DNA damage is a cancer hallmark and contributes to tumorigenesis and chemo/radiotherapeutic resistance. ASPM overexpression has been observed in various cancers ( Xu et al., 2019 , 2020 ; Zhou et al., 2020 ; Alsiary et al., 2014 ; Bruning-Richardson et al., 2011 ; Saleh et al., 2020 ; Xie et al., 2017 ; Tian and Wang, 2020 ; Timaner and Shaked, 2020 ; Hsu et al., 2019 ; Wang et al., 2013 ; Tang et al., 2019 ; Lin et al., 2008 ; Yuan et al., 2020 ; Wu et al., 2021 ) and thus might serve as a prognostic marker in various contexts. ASPM is a positive regulator of the canonical Wnt/β-catenin signaling ( Major et al., 2008 ; Hsu et al., 2019 ) and thus promotes cancer stemness and progression in prostate cancer ( Pai et al., 2019 ) and hepatocellular carcinoma ( Liao et al., 2020 ).…”

Section: Discussionmentioning

confidence: 99%

ASPM promotes homologous recombination-mediated DNA repair by safeguarding BRCA1 stability

Wang

et al. 2021

iScience

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Summary DNA double-strand break (DSB) repair by homologous recombination (HR) is essential for ensuring genome stability. Abnormal spindle-like microcephaly-associated ( ASPM ) gene encodes a spindle protein that is commonly implicated in primary microcephaly. We found that ASPM is recruited to sites of DNA damage in a PARP2-dependent manner. ASPM interacts with BRCA1 and its E3 ligase HERC2, preventing HERC2 from accessing to BRCA1 and ensuring BRCA1 stability. Inhibition of ASPM expression promotes HERC2-mediated BRCA1 degradation, compromises HR repair efficiency and chromosome stability, and sensitizes cancer cells to ionizing radiation. Moreover, we observed a synergistic effect between ASPM and PARP inhibition in killing cancer cells. This research has uncovered a novel function for ASPM in facilitating HR-mediated repair of DSBs by ensuring BRCA1 stability. ASPM might constitute a promising target for synthetic lethality-based cancer therapy.

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Elucidating the roles of ASPM isoforms reveals a novel prognostic marker for pancreatic cancer

Abstract: † Invited commentary for Hsu et al. The differential distributions of ASPM isoforms and their roles in Wnt signaling, cell cycle progression, and pancreatic cancer prognosis.

Cited by 12 publications

References 12 publications

A multi-mode Wnt- and stemness-regulatory module dictated by FOXM1 and ASPM isoform I in gastric cancer

A multi-mode Wnt- and stemness-regulatory module dictated by FOXM1 and ASPM isoform I in gastric cancer

ASPM Is a Prognostic Biomarker and Correlates With Immune Infiltration in Kidney Renal Clear Cell Carcinoma and Liver Hepatocellular Carcinoma

ASPM promotes homologous recombination-mediated DNA repair by safeguarding BRCA1 stability

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