Exploiting the therapeutic vulnerability of IDH-mutant gliomas with zotiraciclib.

Isocitrate dehydrogenase (IDH)-mutant gliomas have distinctive metabolic and biological traits that may render them susceptible to targeted treatments. Here, by conducting a high-throughput drug screen, we pinpointed a specific susceptibility of IDH-mutant gliomas to zotiraciclib (ZTR). ZTR exhibited selective growth inhibition across multiple IDH-mutant glioma in vitro and in vivo models. Mechanistically, ZTR at low doses suppressed CDK9 and RNA Pol II phosphorylation in IDH-mutant cells, disrupting mitochondrial function and NAD+ production, causing oxidative stress. Integrated biochemical profiling of ZTR kinase targets and transcriptomics unveiled that ZTR-induced bioenergetic failure was linked to the suppression of PIM kinase activity. We posit that the combination of mitochondrial dysfunction and an inability to adapt to oxidative stress resulted in significant cell death upon ZTR treatment, ultimately increasing the therapeutic vulnerability of IDH-mutant gliomas. These findings prompted a clinical trial evaluating ZTR in IDH-mutant gliomas towards precision medicine ( NCT05588141 ). Highlights: Zotiraciclib (ZTR), a CDK9 inhibitor, hinders IDH-mutant glioma growth in vitro and in vivo . ZTR halts cell cycle, disrupts respiration, and induces oxidative stress in IDH-mutant cells.ZTR unexpectedly inhibits PIM kinases, impacting mitochondria and causing bioenergetic failure.These findings led to the clinical trial NCT05588141, evaluating ZTR for IDH-mutant gliomas.

Combined inhibition of topoisomerase I and poly(ADP-ribose) polymerase: A synergistic therapeutic strategy for glioblastoma with phosphatase and tensin homolog deficiency.

Background: Deletions or loss-of-function mutations in phosphatase and tensin homolog (PTEN) are common in glioblastoma (GBM) and have been associated with defective DNA damage repair. Here we investigated whether PTEN deficiency presents a vulnerability to a simultaneous induction of DNA damage and suppression of repair mechanisms by combining topoisomerase I (TOP1) and PARP inhibitors. Methods: Patient-derived GBM cells and isogenic PTEN-null and PTEN-WT glioma cells were treated with LMP400 (Indotecan), a novel non-camptothecin TOP1 inhibitor alone and in combination with a PARP inhibitor, Olaparib or Niraparib. RNAseq analysis was performed to identify treatment-induced dysregulated pathways. Results: We found that GBM cells lacking PTEN expression are highly sensitive to LMP400; however, rescue of the PTEN expression reduces sensitivity to the treatment. Combining LMP400 with Niraparib leads to synergistic cytotoxicity by inducing G2/M arrest, DNA damage, suppression of homologous recombination-related proteins, and activation of caspase 3/7 activity significantly more in PTEN-null cells compared to PTEN-WT cells. LMP400 and Niraparib are not affected by ABCB1 and ABCG2, the major ATP-Binding Cassette (ABC) drug efflux transporters expressed at the blood-brain barrier (BBB), thus suggesting BBB penetration which is a prerequisite for potential brain tumor treatment. Animal studies confirmed both an anti-glioma effect and sufficient BBB penetration to prolong survival of mice treated with the drug combination. Conclusions: Our findings provide a proof of concept for the combined treatment with LMP400 and Niraparib in a subset of GBM patients with PTEN deficiency.

Surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy of rectal adenocarcinoma with penile metastasis: a case report.

Background: Despite the rich proximity and vascularization to the pelvic organs, metastatic lesions to the penis are incredibly uncommon. Most primary tumors are genitourinary cancers, and rectal origins are rare. Only 56 cases of metastatic penile tumors have been reported since 1870. Several palliative or curative methods, such as chemotherapy, total penectomy, and radiotherapy, have been applied to treat this condition in previous cases; however, the patient prognosis is poor. Immunotherapy is a beneficial treatment approach for multiple cancers, and recent investigations have shown that it may be beneficial for patients with advanced penile cancer. Case Description: Herein, we report the case of a 59-year-old Chinese man who had metastatic adenocarcinoma in the penile tissue 3 years after rectal cancer resection. The patient presented with penile pain and dysuria for 6 months when he was 54 years old, and Immunohistochemical staining showed that the origin was the rectum after total penectomy. The patient received surgery, chemotherapy, radiotherapy, targeted therapy and immunotherapy positively and still survived for a further 4 years and 6 months following penectomy despite the late metastasis of rectal cancer. There are two major changes and progress after penectomy, all of which have undergone surgical treatment during continuous treatment and follow-up, the patient completed right inguinal lymphadenectomy when his right regional nodes metastasis was found 23 months after penectomy. While the patient suffered from radiation injury after 47 months after penectomy, which led to radiation necrosis and hip soft tissue infection, and the patient tended to lay prone instead of lying on the back because of the hip pain. The patient ultimately died of multiple organ failure. Conclusions: All of the previously reported cases of penile metastasis from rectal cancer since 1870 have been reviewed. Yet, the metastatic prognosis remains poor regardless of the treatment options, except for lesions where metastasis is only limited to the penis. We found that the patient may derive more benefit from strategic therapies including surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy.

Circular RNA circ_0002137 regulated the progression of osteosarcoma through regulating miR-433-3p/ IGF1R axis.

Current clinical treatment targeting osteosarcoma (OS) are limited for OS patients with pulmonary metastasis or relapse, which led to high mortality (70%-85%) for advanced osteosarcoma patients. Although ongoing efforts have been made to illustrate the mechanisms of tumorigenesis and progression in OS; however, it was far for us to learn a comprehensive molecular mechanism implies in OS development. In our study, we implicated a circRNA hsa_circ_0002137, which was higher expressed in osteosarcoma tumours compared with paracancerous tissue. The dysregulated expression pattern was also found in osteosarcoma cell lines. The role of circ_0002137 was explored via down- or up-regulated experiments. It was proved that down-regulation of circ_0002137 suppressed the progress of OS, including cell invasion, cell cycle and cell apoptosis. Furthermore, the correlation between circ_0002137 and miR-433-3p was predicted using bioinformatic tools and verified utilizing RNA pull-down assay and luciferase reporter assay. Interestingly, we found that the inhibitory effect of circ_0002137 on OS was dependent of insulin-like growth factor-1 receptor (IGF1R). In conclusion, it was demonstrated that circ_0002137 could restrain the progression of OS through regulating miR-433-3p/IGF1R axis, providing a comprehensive landscape of circ_0002137 in the generation and development of OS.

Tumor Mutation Burden, Expressed Neoantigens and the Immune Microenvironment in Diffuse Gliomas.

BACKGROUND: A consistent correlation between tumor mutation burden (TMB) and tumor immune microenvironment has not been observed in gliomas as in other cancers. METHODS: Driver germline and somatic mutations, TMB, neoantigen, and immune cell signatures were analyzed using whole exome sequencing (WES) and transcriptome sequencing of tumor and WES of matched germline DNA in a cohort of 66 glioma samples (44 IDH-mutant and 22 IDH-wildtype). RESULTS: Fourteen samples revealed a hypermutator phenotype (HMP). Eight pathogenic (P) or likely pathogenic (LP) germline variants were detected in 9 (19%) patients. Six of these 8 genes were DNA damage repair genes. P/LP germline variants were found in 22% of IDH-mutant gliomas and 12.5% of IDH-wildtype gliomas (p = 0.7). TMB was correlated with expressed neoantigen but showed an inverse correlation with immune score (R = -0.46, p = 0.03) in IDH-wildtype tumors and no correlation in IDH-mutant tumors. The Antigen Processing and Presentation (APP) score correlated with immune score and was surprisingly higher in NHMP versus HMP samples in IDH-wildtype gliomas, but higher in HMP versus NHMP in IDH-mutant gliomas. CONCLUSION: TMB was inversely correlated with immune score in IDH-wildtype gliomas and showed no correlation in IDH-mutant tumors. APP was correlated with immune score and may be further investigated as a biomarker for response to immunotherapy in gliomas. Studies of germline variants in a larger glioma cohort are warranted.

Tumor mutational burden and immunotherapy in gliomas.

Tumor mutational burden (TMB) is an emerging biomarker for the prediction of immunotherapy success in solid tumors. Gliomas, however, do not demonstrate a correlation between TMB and immunotherapy efficacy. Here, we discuss the potential factors influencing this discordance, focusing on the impact of neoantigen immunogenicity, clonality, expression, and presentation.

Targeting CDK9 for the Treatment of Glioblastoma.

Glioblastoma is the most common and aggressive primary malignant brain tumor, and more than two-thirds of patients with glioblastoma die within two years of diagnosis. The challenges of treating this disease mainly include genetic and microenvironmental features that often render the tumor resistant to treatments. Despite extensive research efforts, only a small number of drugs tested in clinical trials have become therapies for patients. Targeting cyclin-dependent kinase 9 (CDK9) is an emerging therapeutic approach that has the potential to overcome the challenges in glioblastoma management. Here, we discuss how CDK9 inhibition can impact transcription, metabolism, DNA damage repair, epigenetics, and the immune response to facilitate an anti-tumor response. Moreover, we discuss small-molecule inhibitors of CDK9 in clinical trials and future perspectives on the use of CDK9 inhibitors in treating patients with glioblastoma.

Phase I Study of Zotiraciclib in Combination with Temozolomide for Patients with Recurrent High-grade Astrocytomas.

PURPOSE: To investigate the toxicity profile and establish an optimal dosing schedule of zotiraciclib with temozolomide in patients with recurrent high-grade astrocytoma. PATIENTS AND METHODS: This two-stage phase I trial determined the MTD of zotiraciclib combined with either dose-dense (Arm1) or metronomic (Arm2) temozolomide using a Bayesian Optimal Interval design; then a randomized cohort expansion compared the progression-free survival rate at 4 months (PFS4) of the two arms for an efficient determination of a temozolomide schedule to combine with zotiraciclib at MTD. Pharmacokinetic and pharmacogenomic profiling were included. Patient-reported outcome was evaluated by longitudinal symptom burden. RESULTS: Fifty-three patients were enrolled. Dose-limiting toxicities were neutropenia, diarrhea, elevated liver enzymes, and fatigue. MTD of zotiraciclib was 250 mg in both arms and thus selected for the cohort expansion. Dose-dense temozolomide plus zotiraciclib (PSF4 40%) compared favorably with metronomic temozolomide (PFS4 25%). Symptom burden worsened at cycle 2 but stabilized by cycle 4 in both arms. A significant decrease in absolute neutrophil count and neutrophil reactive oxygen species production occurred 12-24 hours after an oral dose of zotiraciclib but both recovered by 72 hours. Pharmacokinetic/pharmacogenomic analyses revealed that the CYP1A2_5347T>C (rs2470890) polymorphism was associated with higher AUCinf value. CONCLUSIONS: Zotiraciclib combined with temozolomide is safe in patients with recurrent high-grade astrocytomas. Zotiraciclib-induced neutropenia can be profound but mostly transient, warranting close monitoring rather than treatment discontinuation. Once validated, polymorphisms predicting drug metabolism may allow personalized dosing of zotiraciclib.

S100 calcium-binding protein A9 from tumor-associated macrophage enhances cancer stem cell-like properties of hepatocellular carcinoma.

Tumor-associated macrophages (TAMs) are crucial components of the tumor microenvironment. They play vital roles in hepatocellular carcinoma (HCC) progression. However, the interactions between TAMs and HCC cells have not been fully characterized. In this study, TAMs were induced using human monocytic cell line THP-1 cells in vitro to investigate their functions in HCC progression. S100 calcium-binding protein A9 (S100A9), an inflammatory microenvironment-related secreted protein, was identified to be significantly upregulated in TAMs. S100A9 expression in tumor tissues was associated with poor survival of HCC patients. It could enhance the stem cell-like properties of HepG2 and MHCC-97H cells by activating nuclear factor-kappa B signaling pathway through advanced glycosylation end product-specific receptor in a Ca2+ -dependent manner. Furthermore, we found that, after treatment with S100A9, HepG2 and MHCC-97H cells recruited more macrophages via chemokine (CC motif) ligand 2, which suggests a positive feedback between TAMs and HCC cells. Taken together, our findings reveal that TAMs could upregulate secreted protein S100A9 and enhance the stem cell-like properties of HCC cells and provide a potential therapeutic target for combating HCC.

MerTK inhibition decreases immune suppressive glioblastoma-associated macrophages and neoangiogenesis in glioblastoma microenvironment.

BACKGROUND: Glioblastoma-associated macrophages and microglia (GAMs) are the predominant immune cells in the tumor microenvironment. Activation of MerTK, a receptor tyrosine kinase, polarizes GAMs to an immunosuppressive phenotype, promoting tumor growth. Here, the role of MerTK inhibition in the glioblastoma microenvironment is investigated in vitro and in vivo. METHODS: Effects of MRX-2843 in glioblastoma microenvironment regulation were determined in vitro by cell viability, cytokine array, in vitro tube formation, Western blotting, and wound healing assays. A syngeneic GL261 orthotopic glioblastoma mouse model was used to evaluate the survival benefit of MRX-2843 treatment. Multiplex fluorescent immunohistochemistry was used to evaluate the expression of CD206, an anti-inflammatory marker on GAMs, and angiogenesis in murine brain tumor tissues. RESULTS: MRX-2843 inhibited cell growth and induced apoptosis in human glioblastoma cells and decreased protein expression of phosphorylated MerTK, AKT, and ERK, which are essential for cell survival signaling. Interleukin-8 and C-C motif chemokine ligand 2, the pro-glioma and pro-angiogenic cytokines, were decreased by MRX-2843. Decreased vascular formation and numbers of immunosuppressive (CD206+) GAMs were observed following MRX-2843 treatment in vivo, suggesting that in addition to alleviating immunosuppression, MRX-2843 also inhibits neoangiogenesis in the glioma microenvironment. These results were supported by a prolonged survival in the syngeneic mouse orthotopic GL261 glioblastoma model following MRX-2843 treatment. CONCLUSION: Our findings suggest that MRX-2843 has a therapeutic benefit via promoting GAM polarization away from immunosuppressive condition, inhibiting neoangiogenesis in the glioblastoma microenvironment and inducing tumor cell death.

Case Report: Single-Cell Transcriptomic Analysis of an Anaplastic Oligodendroglioma Post Immunotherapy.

Glioma is the most common primary malignant brain tumor with a poor prognosis. Immune checkpoint inhibitors have been of great interest in investigation of glioma treatments. Here, we report single-cell transcriptomic analyses of two tumor areas from an oligodendroglioma taken from a patient who had multiple tumor recurrences, following several chemotherapies and radiation treatments. The patient subsequently received nivolumab and was considered have disease progression based on conventional diagnostic imaging after two cycles of treatment. He underwent a debulking surgical resection and pathological diagnosis was recurrent disease. During the surgery, tumor tissues were also collected from the enhancing and non-enhancing areas for a scRNAseq analysis to investigate the tumor microenvironment of these radiographically divergent areas. The scRNAseq analysis reveals a plethora of immune cells, suggesting that the increased mass observed on MRI may be partially a result of immune cell infiltration. The patient continued to receive immunotherapy after a short course of palliative radiation and remained free of disease progression for at least 12 months after the last surgery, suggesting a sustained response to immunotherapy. The scRNAseq analysis indicated that the radiological progression was in large part due to immune cell infiltrate and continued immunotherapy led to a positive clinical outcome in a patient who would have otherwise been admitted to hospice care with halting of immunotherapy. Our study demonstrates the potential of scRNAseq analyses in understanding the tumor microenvironment, which may assist the clinical decision-making process for challenging glioma cases following immunotherapy.

ACOT12-Dependent Alteration of Acetyl-CoA Drives Hepatocellular Carcinoma Metastasis by Epigenetic Induction of Epithelial-Mesenchymal Transition.

Metabolic reprogramming plays an important role in supporting tumor growth. However, little is known about the metabolic alterations that promote cancer metastasis. In this study, we identify acyl-CoA thioesterase 12 (ACOT12) as a key player in hepatocellular carcinoma (HCC) metastasis. The expression of ACOT12 is significantly down-regulated in HCC tissues and is closely associated with HCC metastasis and poor survival of HCC patients. Gain- and loss-of-function studies demonstrate that ACOT12 suppresses HCC metastasis both in vitro and in vivo. Further mechanistic studies reveal that ACOT12 regulates the cellular acetyl-CoA levels and histone acetylation in HCC cells and that down-regulation of ACOT12 promotes HCC metastasis by epigenetically inducing TWIST2 expression and the promotion of epithelial-mesenchymal transition. Taken together, our findings link the alteration of acetyl-CoA with HCC metastasis and imply that ACOT12 could be a prognostic marker and a potential therapeutic target for combating HCC metastasis.

Hsa-let-7g promotes osteosarcoma by reducing HOXB1 to activate NF-kB pathway.

MicroRNA (miRNA) is known to be involved in regulating the proliferation, migration and apoptosis of cancer cells in osteosarcoma. In this study, We aim to explore the expression of hsa-let-7 g and its role in pathogenesis of osteosarcoma. By analyzing clinical data. We found high expression of hsa-let-7 g in patients with osteosarcoma. The patients with higher expression of hsa-let-7 g showed poorer prognosis and lower survival rate. After downregulation of hsa-let-7 g in cell model and animal model, we found that with downregulation of hsa-let-7 g, the proliferation of osteosarcoma cells was significantly reduced, the level of migration and invasion was down-regulated, the cell cycle was inhibited, and cell apoptosis was increased. Through Dual Luciferase Reporter, immunohistochemistry, western blot and other experiments, it was found that hsa-let-7 g down-regulated HOXB1 gene and activated NF-kB pathway to promote the development of osteosarcoma. In conclusion, hsa-let-7 g is highly expressed in osteosarcoma tissues, and high expression of hsa-let-7 g can promote the occurrence of osteosarcoma by down-regulating HOXB1 and activating NF-kB pathway.

Pattern of distant metastases in primary extrahepatic bile-duct cancer: A SEER-based study.

Extrahepatic bile duct cancer (EBDC) is a combined type of malignancy mainly consisting of extrahepatic cholangiocarcinoma and gallbladder cancer. Clinically, it is featured with latent symptoms and early metastasis, leading to a poor prognosis. Therefore, this cohort study aimed to depict the possible metastatic patterns of EBDC of diverse sub-types and evaluate the prognostic significance of diverse metastatic destinations with data from the clinical database. Relevant data of total 4061 confirmed EBDC patients diagnosed between 2010 and 2013 from the Surveillance, Epidemiology and End Results (SEER) database was obtained. We applied t test to describe the baseline data of patients included and used chi-square test to compare the distribution of distant metastatic sites. We further adopted odds ratio assess the combined metastatic patterns and compared survival difference of patients with different distal metastasis organ by Kaplan-Meier analysis. We identified totally 4061 patients over 18 years old diagnosed with extrahepatic bile tract malignancies between 2010 and 2013, with clear metastatic status and follow-up data, without primary malignancies. Liver and distant lymph (DL) are the two most common sites as a single metastasis organ. In combined metastasis patterns, bi-organ is more frequent than the other types. Lung is the organ preferentially for bi-organ metastasis, while bone and distant lymph similarly intend to co-metastasize with brain. Distal metastasis in EBDC patients indicates an extremely poor prognosis. According to the final analysis results, malignancies in extrahepatic bile duct exhibit similar metastatic patterns, suggesting that we can regard them as a unity to assess its development. Profound differences exist in distribution of distant extrahepatic metastatic sites and their combinations. Results from our studies would provide some information for follow-up strategies and future studies.

RA190, a Proteasome Subunit ADRM1 Inhibitor, Suppresses Intrahepatic Cholangiocarcinoma by Inducing NF-KB-Mediated Cell Apoptosis.

BACKGROUND/AIMS: Effective drug treatment for intrahepatic cholangiocarcinoma (ICC) is currently lacking. Therefore, there is an urgent need for new targets and new drugs that can prolong patient survival. Recently targeting the ubiquitin proteasome pathway has become an attractive anti-cancer strategy. In this study, we aimed to evaluate the therapeutic effect of and identify the potential mechanisms involved in targeting the proteasome subunit ADRM1 for ICC. METHODS: The expression of ADRM1 and its prognostic value in ICC was analyzed using GEO and TCGA datasets, tumor tissues, and tumor tissue arrays. The effects of RA190 on the proliferation and survival of both established ICC cell lines and primary ICC cells were examined in vitro. Annexin V/propidium iodide staining, western blotting and immunohistochemical staining were performed. The in vivo anti-tumor effect of RA190 on ICC was validated in subcutaneous xenograft and patient-derived xenograft (PDX) models. RESULTS: ADRM1 levels were significantly higher in ICC tissues than in normal bile duct tissues. ICC patients with high ADRM1 levels had worse overall survival (hazard ratio [HR] = 2.383, 95% confidence interval [CI] =1.357 to 4.188) and recurrence-free survival (HR = 1.710, 95% CI =1.045 to 2.796). ADRM1 knockdown significantly inhibited ICC growth in vitro and in vivo. The specific inhibitor RA190 targeting ADRM1 suppressed proliferation and reduced cell vitality of ICC cell lines and primary ICC cells significantly in vitro. Furthermore, RA190 significantly inhibited the proteasome by inactivating ADRM1, and the consequent accumulation of ADRM1 substrates decreased the activating levels of NF-κB to aggravate cell apoptosis. The therapeutic benefits of RA190 treatment were further demonstrated in both subcutaneous implantation and PDX models. CONCLUSIONS: Our findings indicate that up-regulated ADRM1 was involved in ICC progression and suggest the potential clinical application of ADRM1 inhibitors (e.g., RA190 and KDT-11) for ICC treatment.

LINC00968 functions as an oncogene in osteosarcoma by activating the PI3K/AKT/mTOR signaling.

Osteosarcoma is recognized as a malignant tumor in the skeletal system. Long non-coding RNAs (lncRNAs) have been exhibited to play crucial roles in osteosarcoma development. Our current study focused on the biological effects and mechanism of LINC00968 in osteosarcoma pathogenesis. We observed that LINC00968 was dramatically elevated in osteosarcoma cells including U2OS, MG63, Saos-2, SW1353, and 143-B cells compared to human osteoblast cell line hFOB. Silence of LINC00968 inhibited osteosarcoma cell growth and proliferation in vitro. Reversely, overexpression of LINC00968 promoted osteosarcoma cell survival and cell colony formation ability in Saos-2 and 143-B cells. In addition, LINC00968 was able to induce osteosarcoma cell migration and invasion through up-regulating MMP-2 and MMP-9 protein levels. The phosphoinosmde-3-kinase/Protein Kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway has been reported to participate in several cancer types. Here, in our study, we found that PI3K/AKT/mTOR pathway was involved in osteosarcoma progression. Knockdown of LINC00968 inactivated PI3K/AKT/mTOR signaling pathway in vitro. Subsequently, in vivo tumor xenografts were established using 143-B cells to investigate whether LINC00968 can induce osteosarcoma development in vivo. Consistently, it was indicated that inhibition of LINC00968 significantly inhibited osteosarcoma progression in vivo. Taken these together, in our research, LINC00968 could be provided as a novel prognostic biomarker and therapeutic target in osteosarcoma diagnosis and treatment.

Long non-coding RNA ANRIL is associated with a poor prognosis of osteosarcoma and promotes tumorigenesis via PI3K/Akt pathway.

AIM: Increasing evidence has shown that long noncoding RNAs (lncRNAs) ANRIL may function as oncogenes in various types of malignancies. However, there is still a lack of knowledge concerning its role in osteosarcoma (OS). In this study, we aimed to investigate the influence of ANRIL on cell proliferation and invasion of OS and to determine its association with clinicopathological features of the patients. METHODS: The tumor specimens and the adjacent normal tissues were collected from 57 OS patients and the expression level of ANRIL was quantified by RT-qPCR. High expression of ANRIL was defined as a relative mRNA expression of > 1.5 fold (tumor/normal). Knockdown of ANRIL was performed in human OS cell lines to investigate its influence on cell proliferation, apoptosis and invasion. In addition, expression of downstream genes in the transfected cells were determined by Western blot. RESULTS: The expression level of ANRIL was significantly increased in OS tissues than in the adjacent normal tissues. 33 patients were included in the high expression group and the other 24 patients were included in the normal expression group. ANRIL expression was significantly associated with tumor size (5.7 cm ±â€¯2.4 cm vs. 4.3 cm ±â€¯1.7 cm, p = 0.02) and the 5-year survival rate (51.5% vs. 79.1%, p = 0.03). Knockdown of ANRIL could significantly induce cell apoptosis and inhibit cell proliferation and invasion. Moreover, knockdown of ANRIL could significantly decrease the expression level of phosphorylated PI3K and AKT in OS cells. CONCLUSIONS: Upregulated expression of ANRIL is associated with the tumor development and prognosis of OS. ANRIL may regulate the function of OS cells through the AKT pathway.

Elevated G6PD expression contributes to migration and invasion of hepatocellular carcinoma cells by inducing epithelial-mesenchymal transition.

Altered metabolism is one of the hallmarks of cancer cells. Pentose phosphate pathway (PPP) is a fundamental component of cellular metabolism. Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP, is elevated in many cancers and contributes to tumor growth by producing ribose-5-phosphate and NADPH through PPP. However, the role of G6PD in hepatocellular carcinoma (HCC) metastasis and the clinical significance of G6PD in HCC progression and prognosis have not been well determined. In this study, by investigating tissue samples from HCC patients and HCC cell lines, we found that elevated G6PD expression is significantly associated with HCC metastasis and poor prognosis of HCCs, and that knockdown of G6PD inhibits in vitro proliferation, migration and invasion of HCC cell lines. Further studies reveal that G6PD contributes to HCC migration and invasion of hepatocellular carcinoma cells by inducing epithelial-mesenchymal transition through activation of signal transducer and activator of transcription 3 (STAT3) pathway. Our findings suggest that targeting G6PD could open up possibilities for metastasis intervention and improve the patients' outcomes for HCC.

Suppression of glioblastoma by targeting the overactivated protein neddylation pathway.

BACKGROUND: The neddylation pathway has been recently identified as an attractive anticancer target, and MLN4924, a specific NEDD8-activating enzyme inhibitor, has been developed as a first-in-class anticancer agent. However, neither the status of the neddylation pathway in glioblastoma (GBM) nor the effect of MLN4924 against GBM has been systematically investigated yet. METHODS: To measure the activation state of the neddylation pathway in GBM, expression of the NEDD8-activating enzyme (E1), NEDD8-conjugating enzyme (E2), and global protein neddylation in GBM tumor tissues versus adjacent tissues were examined by immunoblotting analysis and immunohistochemistry staining. To assess the therapeutic efficacy of neddylation inhibition in GBM, cell proliferation in vitro and tumor growth in vivo were determined upon neddylation inhibition by MLN4924, an investigational NEDD8-activating enzyme inhibitor. RESULTS: The neddylation pathway was overactivated in a majority of GBM tumor tissues when compared with adjacent normal tissues. The upregulation of this pathway in GBM tissues was positively correlated with high-grade disease and postoperative recurrence but was negatively associated with patient overall survival. MLN4924 treatment inhibited cullin neddylation, inactivated cullin-RING E3 ligase, and led to the accumulation of tumor-suppressive cullin-RING E3 ligase substrates to trigger cell-cycle arrest and senescence or apoptosis in a cell-line dependent manner. Moreover, inhibition of neddylation by MLN4924 significantly suppressed tumor growth in an orthotopic xenograft model of human GBM. CONCLUSION: Our study indicates that an overactivated neddylation pathway may be involved in GBM progression and that inhibition of this oncogenic pathway is a potentially new therapeutic approach for GBM.