Clinicopathological Analysis and Treatment of Adult Patients with Inflammatory Myofibroblastic Tumor: A 15-Year Single- Center Study.

PURPOSE: Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal malignancy that occurs primarily in children and adolescents. The clinical and pathological features of IMT in adult patients are not well understood. Materials and Methods: We retrospectively searched for records of adult patients with IMT at Fudan University Shanghai Cancer Center from 2006 to 2021. Clinicopathological data, treatments, and outcomes were collected and analyzed. RESULTS: Thirty adult patients with IMT, mostly women (60.0%), were included. The median age of the patients was 38 (21-77). The most common primary site was abdominopelvic region (53.3%), followed by lungs (20.0%). Seven patients had an abdominal epithelioid inflammatory myofibroblast sarcoma (EIMS). The positivity rate of anaplastic lymphoma kinase (ALK) was 81.5% (22/27). Sixteen patients with advanced ALK-positive disease received crizotinib, with an objective response rate (ORR) of 81.3% and a disease control rate of 87.5%. The median progression-free survival was 20.8 months. EIMS was associated with more aggressive behavior; however, the prognosis was similar to that of non-EIMS patients after treatment with an ALK inhibitor. At a median follow-up time of 30 months (95% confidence interval [CI], 13.6 to 46.4), the 5-year overall survival was 77% (95% CI, 66 to 88) in all patients. CONCLUSION: Adult IMTs appeared more aggressive, with a higher incidence of recurrence and metastases, and patients with EIMS had more aggressive cases. Treatment with ALK inhibitors resulted in a high ORR and a durable response, which suggested that ALK inhibitors could be used as a first-line treatment option in adult patients with ALK-positive advanced IMT.

PUMA facilitates EMI1-promoted cytoplasmic Rad51 ubiquitination and inhibits DNA repair in stem and progenitor cells.

Maintenance of genetic stability via proper DNA repair in stem and progenitor cells is essential for the tissue repair and regeneration, while preventing cell transformation after damage. Loss of PUMA dramatically increases the survival of mice after exposure to a lethal dose of ionizing radiation (IR), while without promoting tumorigenesis in the long-term survivors. This finding suggests that PUMA (p53 upregulated modulator of apoptosis) may have a function other than regulates apoptosis. Here, we identify a novel role of PUMA in regulation of DNA repair in embryonic or induced pluripotent stem cells (PSCs) and immortalized hematopoietic progenitor cells (HPCs) after IR. We found that PUMA-deficient PSCs and HPCs exhibited a significant higher double-strand break (DSB) DNA repair activity via Rad51-mediated homologous recombination (HR). This is because PUMA can be associated with early mitotic inhibitor 1 (EMI1) and Rad51 in the cytoplasm to facilitate EMI1-mediated cytoplasmic Rad51 ubiquitination and degradation, thereby inhibiting Rad51 nuclear translocation and HR DNA repair. Our data demonstrate that PUMA acts as a repressor for DSB DNA repair and thus offers a new rationale for therapeutic targeting of PUMA in regenerative cells in the context of DNA damage.

Circ-EPB41L5 regulates the host gene EPB41L5 via sponging miR-19a to repress glioblastoma tumorigenesis.

BACKGROUND: Circular RNAs (circRNAs) are widely expressed non-coding RNAs in eukaryotic cells, involved in regulating tumorigenesis of several types of cancers. However, the expression profiles and the precise functional role in glioblastoma remain unclear. RESULTS: Circ-EPB41L5 was downregulated in glioblastoma tissues and cell lines compared to the normal brain tissues and cell lines. Low circ-EPB41L5 expression was correlated to the poor prognosis of glioblastoma patients, while the overexpression inhibited proliferation, clone formation, migration, and invasion abilities of glioma cells, and the suppression had counter effects. Furthermore, RNA-seq results determined that the host gene was the target gene of circ-EPB41L5, which served as a sponge against miR-19a and inhibited miR-19a activity from upregulating the expression of EPB41L5. Finally, we found that circ-EPB41L5 regulated the RhoC expression and phosphorylation of AKT through EPB41L5. CONCLUSION: The current study highlights a novel suppressive function of circ-EPB41L5 and reveals that circ-EPB41L5/miR-19a/EPB41L5/p-AKT regulatory axis plays a striking role in the progression of glioblastoma, which provides a novel insight into the mechanisms underlying glioblastoma. METHODS: The expression profiles of circRNAs in glioblastoma were determined by Illumina HiSeq from six glioblastoma tissues and six normal brain tissues. Then, the correlation between circ-EPB41L5 expression and clinical features and the survival time of 45 glioblastoma patients was detected. The interaction between circ-EPB41L5, miR-19a, and EPB41L5 was assessed by luciferase reporter and RNA pull-down assays. The effects of expression of the ectopic intervention of circ-EPB41L5 or EPB41L5 on proliferation, clone formation, migration, and invasion in vitro and tumorigenesis in vivo were observed to evaluate the function of circ-EPB41L5 or EPB41L5.

CDK5-dependent phosphorylation and nuclear translocation of TRIM59 promotes macroH2A1 ubiquitination and tumorigenicity.

Despite the development of adjuvant therapies, glioblastoma (GBM) patients remain incurable, thus justifying the urgent need of new therapies. CDK5 plays a critical role in GBM and is a potential target for GBM. However, the mechanism by which CDK5 promotes GBM tumorigenicity remains largely unknown. Here, we identify TRIM59 as a substrate of CDK5. EGFR-activated CDK5 directly binds to and phosphorylates TRIM59, a ubiquitin ligase at serine 308, which recruits PIN1 for cis-trans isomerization of TRIM59, leading to TRIM59 binding to importin α5 and nuclear translocation. Nuclear TRIM59 induces ubiquitination and degradation of the tumor suppressive histone variant macroH2A1, leading to enhanced STAT3 signaling activation and tumorigenicity. These findings are confirmed by inhibition of CDK5-activated TRIM59 activity that results in suppression of intracranial tumor growth. Correlative expressions of the components of this pathway are clinically prognostic. Our findings suggest targeting CDK5/TRIM59 signaling axis as a putative strategy for treating GBM.

Targeting PDGFRα-activated glioblastoma through specific inhibition of SHP-2-mediated signaling.

BACKGROUND: Glioblastoma (GBM) is the most malignant primary brain tumor, with dismal median survival. Treatment of GBM is particularly challenging given the intrinsic resistance to chemotherapy and difficulty of drugs to reach the tumor beds due to the blood-brain barrier. Here, we examined the efficacy of SHP099, a potent, selective, and oral SHP-2 inhibitor for treating GBM with activated platelet derived growth factor receptor alpha (PDGFRα) signaling. METHODS: The effects of SHP099 on cell survival of neural progenitor cells (NPCs), GBM cell lines, and patient-derived glioma stem-like cells (GSCs) were evaluated. Brain and plasma pharmacokinetics of SHP099 and its ability to inhibit SHP-2 signaling were assessed. SHP099 efficacy as a single agent or in combination with temozolomide (TMZ) was assessed using transformed mouse astrocyte and GSC orthotopic xenograft models. RESULTS: Activated PDGFRα signaling in established GBM cells, GSCs, and transformed mouse astrocytes was significantly inhibited by SHP099 compared with NPCs in vitro and in vivo through targeting SHP-2-stimulated activation of extracellular signal-regulated protein kinases 1 and 2 in GBM. SHP099 treatment specifically inhibited expression of JUN, a downstream effector of PDGFR signaling, thereby attenuating cell cycle progression in GBM cells with activated PDGFRα. Moreover, SHP099 accumulated at efficacious concentrations in the brain and effectively inhibited orthotopic GBM tumor xenograft growth. SHP099 exhibited antitumor activity either as a single agent or in combination with TMZ and provided significant survival benefits for GBM tumor xenograft-bearing animals. CONCLUSIONS: Our data demonstrate the utility and feasibility of SHP099 as a potential therapeutic option for improving the clinical treatment of GBM in combination with TMZ.

LncRNA PVT1 regulates triple-negative breast cancer through KLF5/beta-catenin signaling.

ABSTACT: Recent molecularly targeted approach gains advance in breast cancer treatment. However, the estimated 5-year survival rate has not met the desired expectation for improvement, especially for patients with triple-negative breast cancer (TNBC). Here we report that the lncRNA PVT1 promotes KLF5/beta-catenin signaling to drive TNBC tumorigenesis. PVT1 is upregulated in clinical TNBC tumors. Using genetic approaches targeting PVT1 in TNBC cells, we found that PVT1 depletion inhibited cell proliferation, colony formation, and orthotopic xenograft tumor growth. Mechanistically, PVT1 binds with KLF5 and increases its stability via BAP1, which upregulates beta-catenin signaling, resulting in enhanced TNBC tumorigenesis. PVT1, KLF5, and beta-catenin were also revealed to be co-expressed in clinical TNBC samples. Our findings uncover a new singaling pathway to mediate TNBC, and provide PVT1 as a new target for improving treatment of TNBC.

TRIM59 Promotes Gliomagenesis by Inhibiting TC45 Dephosphorylation of STAT3.

Aberrant EGFR signaling is a common driver of glioblastoma (GBM) pathogenesis; however, the downstream effectors that sustain this oncogenic pathway remain unclarified. Here we demonstrate that tripartite motif-containing protein 59 (TRIM59) acts as a new downstream effector of EGFR signaling by regulating STAT3 activation in GBM. EGFR signaling led to TRIM59 upregulation through SOX9 and enhanced the interaction between TRIM59 and nuclear STAT3, which prevents STAT3 dephosphorylation by the nuclear form of T-cell protein tyrosine phosphatase (TC45), thereby maintaining transcriptional activation and promoting tumorigenesis. Silencing TRIM59 suppresses cell proliferation, migration, and orthotopic xenograft brain tumor formation of GBM cells and glioma stem cells. Evaluation of GBM patient samples revealed an association between EGFR activation, TRIM59 expression, STAT3 phosphorylation, and poor prognoses. Our study identifies TRIM59 as a new regulator of oncogenic EGFR/STAT3 signaling and as a potential therapeutic target for GBM patients with EGFR activation.Significance: These findings identify a novel component of the EGFR/STAT3 signaling axis in the regulation of glioma tumorigenesis. Cancer Res; 78(7); 1792-804. ©2018 AACR.

Histone Acetyltransferase KAT6A Upregulates PI3K/AKT Signaling through TRIM24 Binding.

Lysine acetyltransferase KAT6A is a chromatin regulator that contributes to histone modification and cancer, but the basis of its actions are not well understood. Here, we identify a KAT6A signaling pathway that facilitates glioblastoma (GBM), where it is upregulated. KAT6A expression was associated with GBM patient survival. KAT6A silencing suppressed cell proliferation, cell migration, colony formation, and tumor development in an orthotopic mouse xenograft model system. Mechanistic investigations demonstrated that KAT6A acetylates lysine 23 of histone H3 (H3K23), which recruits the nuclear receptor binding protein TRIM24 to activate PIK3CA transcription, thereby enhancing PI3K/AKT signaling and tumorigenesis. Overexpressing activated AKT or PIK3CA rescued the growth inhibition due to KAT6A silencing. Conversely, the pan-PI3K inhibitor LY294002 abrogated the growth-promoting effect of KAT6A. Overexpression of KAT6A or TRIM24, but not KAT6A acetyltransferase activity-deficient mutants or TRIM24 mutants lacking H3K23ac-binding sites, promoted PIK3CA expression, AKT phosphorylation, and cell proliferation. Taken together, our results define an essential role of KAT6A in glioma formation, rationalizing its candidacy as a therapeutic target for GBM treatment. Cancer Res; 77(22); 6190-201. ©2017 AACR.

The role and mechanism of CRL4 E3 ubiquitin ligase in cancer and its potential therapy implications.

CRLs (Cullin-RING E3 ubiquitin ligases) are the largest E3 ligase family in eukaryotes, which ubiquitinate a wide range of substrates involved in cell cycle regulation, signal transduction, transcriptional regulation, DNA damage response, genomic integrity, tumor suppression and embryonic development. CRL4 E3 ubiquitin ligase, as one member of CRLs family, consists of a RING finger domain protein, cullin4 (CUL4) scaffold protein and DDB1-CUL4 associated substrate receptors. The CUL4 subfamily includes two members, CUL4A and CUL4B, which share extensively sequence identity and functional redundancy. Aberrant expression of CUL4 has been found in a majority of tumors. Given the significance of CUL4 in cancer, understanding its detailed aspects of pathogenesis of human malignancy would have significant value for the treatment of cancer. Here, the work provides an overview to address the role of CRL4 E3 ubiquitin ligase in cancer development and progression, and discuss the possible mechanisms of CRL4 ligase involving in many cellular processes associated with tumor. Finally, we discuss its potential value in cancer therapy.