p53-responsive CMBL reprograms glucose metabolism and suppresses cancer development by destabilizing phosphofructokinase PFKP.

Aerobic glycolysis is critical for cancer progression and can be exploited in cancer therapy. Here, we report that the human carboxymethylenebutenolidase homolog (carboxymethylenebutenolidase-like [CMBL]) acts as a tumor suppressor by reprogramming glycolysis in colorectal cancer (CRC). The anti-cancer action of CMBL is mediated through its interactions with the E3 ubiquitin ligase TRIM25 and the glycolytic enzyme phosphofructokinase-1 platelet type (PFKP). Ectopic CMBL enhances TRIM25 binding to PFKP, leading to the ubiquitination and proteasomal degradation of PFKP. Interestingly, CMBL is transcriptionally activated by p53 in response to genotoxic stress, and p53 activation represses glycolysis by promoting PFKP degradation. Remarkably, CMBL deficiency, which impairs p53's ability to inhibit glycolysis, makes tumors more sensitive to a combination therapy involving the glycolysis inhibitor 2-deoxyglucose. Taken together, our study demonstrates that CMBL suppresses CRC growth by inhibiting glycolysis and suggests a potential combination strategy for the treatment of CMBL-deficient CRC.

Involvement of spleen is associated with shorter survival in patients with angioimmunoblastic T cell lymphoma.

BACKGROUND: The prognosis of patients with angioimmunoblastic T cell lymphoma (AITL) remains dismal, with their 5-year overall survival (OS) and progression-free survival (PFS) rates of 32-41% and 18-38%, respectively. Spleen involvement occurs in a proportion of patients with AITL. But still, it is unclear whether spleen involvement impacts the prognosis of AITL patients. In this study, we aim to establish new prognostic indicators for the identification of high-risk patients to draft optimal treatment regimens. METHODS: We collected and counted the clinical data of 54 patients with AITL treated with CHOP-based first-line chemotherapy regimen between 2010 and 2021 at Hubei Cancer Hospital and Hunan Cancer Hospital. In addition, all patients received PET-CT scan prior to receiving treatment. We performed univariate and multivariate analyses to assess the predictive role of tumor characteristics, laboratory, and radiographic data for the prognosis of AITL. RESULTS: We observed that PFS and OS are worse in patients with high ECOG scores, spleen involvement, and low serum albumin levels in patients with AITL. In univariate analysis, stage (HR 3.515 [1.142-10.822], p = 0.028) and spleen involvement (HR 8.378 [1.085-64.696, p = 0.042) were correlated with PFS in patients with AITL. Besides, stage (HR 3.439 [1.108-10.674], p = 0.033) and spleen involvement (HR 11.002 [1.420-85.254], p = 0.022) were significantly correlated with OS. Consistently, spleen involvement was correlated with OS (HR 16.571 [1.350-203.446], p = 0.028) and PFS (HR 10.905 [1.037-114.690], p = 0.047) in AITL patients in a multivariate analysis. CONCLUSION: This study demonstrates that spleen involvement might be used as a prognostic indicator for AITL patients.

UTP11 deficiency suppresses cancer development via nucleolar stress and ferroptosis.

The eukaryotic ribosome is essential for cancer cell survival. Perturbation of ribosome biogenesis induces nucleolar stress or ribosomal stress, which restrains cancer growth, as rapidly proliferating cancer cells need more active ribosome biogenesis. In this study, we found that UTP11 plays an important role in the biosynthesis of 18S ribosomal RNAs (rRNA) by binding to the pre-rRNA processing factor, MPP10. UTP11 is overexpressed in human cancers and associated with poor prognoses. Interestingly, depletion of UTP11 inhibits cancer cell growth in vitro and in vivo through p53-depedednt and -independent mechanisms, whereas UTP11 overexpression promotes cancer cell growth and progression. On the one hand, the ablation of UTP11 impedes 18S rRNA biosynthesis to trigger nucleolar stress, thereby preventing MDM2-mediated p53 ubiquitination and degradation through ribosomal proteins, RPL5 and RPL11. On the other hand, UTP11 deficiency represses the expression of SLC7A11 by promoting the decay of NRF2 mRNA, resulting in reduced levels of glutathione (GSH) and enhanced ferroptosis. Altogether, our study uncovers a critical role for UTP11 in maintaining cancer cell survival and growth, as depleting UTP11 leads to p53-dependent cancer cell growth arrest and p53-independent ferroptosis.

Association of blood lead with estradiol and sex hormone-binding globulin in 8-19-year-old children and adolescents.

Background: Metals can interfere with hormonal functioning through indirect mechanisms and by binding at the receptor site; thus, they may be associated with hormonal changes. However, there have been few studies on the health impact of metal exposure among children and adolescents. Thus, we aimed to examine the associations of blood lead level (BLL) with estradiol (E2) and sex hormone-binding globulin (SHBG) among children and adolescents aged 8-19 years in the National Health and Nutrition Examination Survey (NHANES) database. Methods: This was a cohort study of 2188 individuals from the NHANES. BLL was taken as independent variables, E2 and SHBG as dependent variable. We conducted weighted multivariate linear regression models and smooth curve fittings to evaluate the association between them. Results: The BLL was significantly positively associated with serum SHBG level in females, especially when the LnBLL quartiles are between Q3 and Q4. There was an inverted U-shaped association between BLL and E2 with the point of inflection at 1.86 µg/L and a U-shaped association between BLL and SHBG with the point of inflection at 1.86 µg/L in female adolescents aged 16-19 years. Meanwhile, In males, there was a positive trend of correlation between BLL and E2 in the 8-11 years, and 16-19 years groups. Conclusions: This study found an inverted U-shaped association of BLL with E2 and a U-shaped association between BLL and SHBG in female adolescents aged 16-19 years. This indicates that adjusting blood lead exposure to mitigate the effects of lead on growth and development is important for adolescents aged 16-19 years. Controlling the BLL below 1.86 µg/L may minimize the damage to E2.

5mC-Related lncRNAs as Potential Prognostic Biomarkers in Colon Adenocarcinoma.

Globally, colon adenocarcinoma (COAD) is one of the most frequent types of malignant tumors. About 40~50% of patients with advanced colon adenocarcinoma die from recurrence and metastasis. Long non-coding RNAs (lncRNAs) and 5-methylcytosine (5mC) regulatory genes have been demonstrated to involve in the progression and prognosis of COAD. The goal of this study was to explore the biological characteristics and potential predictive value of 5mC-related lncRNA signature in COAD. In this research, The Cancer Genome Atlas (TCGA) was utilized to obtain the expression of genes and somatic mutations in COAD, and Pearson correlation analysis was used to select lncRNAs involved in 5mC-regulated genes. Furthermore, we applied univariate Cox regression and Lasso Cox regression to construct 5mC-related lncRNA signature. Then Kaplan-Meier survival analysis, principal components analysis (PCA), receiver operating characteristic (ROC) curve, and a nomogram were performed to estimate the prognostic effect of the risk signature. GSEA was utilized to predict downstream access of the risk signature. Finally, the immune characteristics and immunotherapeutic signatures targeting this risk signature were analyzed. In the results, we obtained 1652 5mC-related lncRNAs by Pearson correlation analysis in the TCGA database. Next, we selected a risk signature that comprised 4 5mC-related lncRNAs by univariate and Lasso Cox regression. The prognostic value of the risk signature was proven. Finally, the biological mechanism and potential immunotherapeutic response of the risk signature were identified. Collectively, we constructed the 5mC-related lncRNA risk signature, which could provide a novel prognostic prediction of COAD patients.

LncRNA RNA Component of Mitochondrial RNA-Processing Endoribonuclease Promotes AKT-Dependent Breast Cancer Growth and Migration by Trapping MicroRNA-206.

The RNA component of mitochondrial RNA-processing endoribonuclease (RMRP) was recently shown to play a role in cancer development. However, the function and mechanism of RMRP during cancer progression remain incompletely understood. Here, we report that RMRP is amplified and highly expressed in various malignant cancers, and the high level of RMRP is significantly associated with their poor prognosis, including breast cancer. Consistent with this, ectopic RMRP promotes proliferation and migration of TP53-mutated breast cancer cells, whereas depletion of RMRP leads to inhibition of their proliferation and migration. RNA-seq analysis reveals AKT as a downstream target of RMRP. Interestingly, RMRP indirectly elevates AKT expression by preventing AKT mRNA from miR-206-mediated targeting via a competitive sequestering mechanism. Remarkably, RMRP endorses breast cancer progression in an AKT-dependent fashion, as knockdown of AKT completely abolishes RMRP-induced cancer cell growth and migration. Altogether, our results unveil a novel role of the RMRP-miR-206-AKT axis in breast cancer development, providing a potential new target for developing an anti-breast cancer therapy.

Inactivation of the tumor suppressor p53 by long noncoding RNA RMRP.

p53 inactivation is highly associated with tumorigenesis and drug resistance. Here, we identify a long noncoding RNA, the RNA component of mitochondrial RNA-processing endoribonuclease (RMRP), as an inhibitor of p53. RMRP is overexpressed and associated with an unfavorable prognosis in colorectal cancer. Ectopic RMRP suppresses p53 activity by promoting MDM2-induced p53 ubiquitination and degradation, while depletion of RMRP activates the p53 pathway. RMRP also promotes colorectal cancer growth and proliferation in a p53-dependent fashion in vitro and in vivo. This anti-p53 action of RMRP is executed through an identified partner protein, SNRPA1. RMRP can interact with SNRPA1 and sequester it in the nucleus, consequently blocking its lysosomal proteolysis via chaperone-mediated autophagy. The nuclear SNRPA1 then interacts with p53 and enhances MDM2-induced proteasomal degradation of p53. Remarkably, ablation of SNRPA1 completely abrogates RMRP regulation of p53 and tumor cell growth, indicating that SNRPA1 is indispensable for the anti-p53 function of RMRP. Interestingly and significantly, poly (ADP-ribose) polymerase (PARP) inhibitors induce RMRP expression through the transcription factor C/EBPß, and RMRP confers tumor resistance to PARP inhibition by preventing p53 activation. Altogether, our study demonstrates that RMRP plays an oncogenic role by inactivating p53 via SNRPA1 in colorectal cancer.

p53 induces ARTS to promote mitochondrial apoptosis.

Apoptosis related protein in TGF-ß signaling pathway (ARTS) was originally discovered in cells undergoing apoptosis in response to TGF-ß, but ARTS also acts downstream of many other apoptotic stimuli. ARTS induces apoptosis by antagonizing the anti-apoptotic proteins XIAP and Bcl-2. Here we identified the pro-apoptotic Sept4/ARTS gene as a p53-responsive target gene. Ectopic p53 and a variety of p53-inducing agents increased both mRNA and protein levels of ARTS, whereas ablation of p53 reduced ARTS expression in response to multiple stress conditions. Also, γ-irradiation induced p53-dependent ARTS expression in mice. Consistently, p53 binds to the responsive DNA element on the ARTS promoter and transcriptionally activated the promoter-driven expression of a luciferase reporter gene. Interestingly, ARTS binds to and sequesters p53 at mitochondria, enhancing the interaction of the latter with Bcl-XL. Ectopic ARTS markedly augments DNA damage stress- or Nutlin-3-triggered apoptosis, while ablation of ARTS preferentially impairs p53-induced apoptosis. Altogether, these findings demonstrate that ARTS collaborates with p53 in mitochondria-engaged apoptosis.

Targeted regulation of MiR-98 on E2F1 increases chemosensitivity of leukemia cells K562/A02.

BACKGROUND: miRNA is a microRNA that negatively regulates protein expression at post-transcriptional or translational level. It is widely involved in the pathogenesis of tumors. miR-98 belongs to the let-7 family, and its overexpression can increase the sensitivity to drugs in solid cancer cells. However, the function of miR-98 in leukemia is still unclear. In this study, the effect of miR-98 on drug resistance and proliferation of leukemia cells were investigated. METHODS: Real-time quantitative polymerase chain reaction analyzed the expression difference between miR-98 and E2F1 in leukemia cell lines, K562 and K562/A02. The downstream target gene of miR-98 was predicted by TargetScan; K562/A02 was transiently transfected with miR-98 mimic to upregulate the expression of miR-98; real-time quantitative polymerase chain reaction and Western blot were used to analyze the expression alterations of E2F1; cell counting kit-8 was used to evaluate the influence on K562/A02 proliferation and sensitivity to chemotherapeutic drugs; meanwhile, Western blot was used to analyze the expression of p21, Bax, matrix metalloproteinase 9 and ABCG2 proteins. RESULTS: E2F1 is one of the target genes of miR-98 proved by bioinformatics. Compared with the K562, the level of miRNA-98 expression was decreased in K562/A02, but the level of E2F1 expression was upregulated. Leukemia cell line K562/A02 was transfected with miR-98 mimic to upregulate the expression of miR-98, the expression of E2F1 was significantly decreased. After upregulating the miR-98 expression in K562/A02, the proliferation was weakened, and the sensitivity to chemotherapy was increased. Western blot showed that upregulated miR-98 expression increased the levels of p21 and BAX proteins in K562/A02 cells, and decreased the levels of matrix metalloprotease 9 and ABCG2 proteins, which were significantly different compared with those before miR-98 mimic transfection. CONCLUSION: In the leukemia drug-resistant cell line K562/A02, the targeted upregulated expression of miR-98 could decrease the proliferation of leukemia cells and improve the sensitivity to chemotherapeutics by inhibiting E2F1 expression. miR-98 might be a potential target for overcoming leukemia multidrug resistance.

[Circulating Serum MicroRNA as Diagnostic Biomarkers for Multiple Myeloma].

OBJECTIVE: To investigate the diagnostic value of circulating serum miRNA for multiple myeloma. METHODS: Forty blood samples from patients with multiple myeloma were collected from July 2013 to June 2014 in Department of Hematology, Zhongshan Hospital Affiliated to Xiamen University. The real-time quantitative PCR was performed to detect the serum expression levels of miRNAs (miR-29a, miR-155, miR-16 and miR-92a) circulating in the different stages of patients with multiple myeloma and evaluate the diagnostic value for patients with multiple myeloma. RESULTS: The serum level of miR-29a significantly increased in newly diagnosed patients as compared to healthy donor (P<0.01), serum miR-155 levels were significantly lower as compared with healthy donor(P<0.001); The ratio of miR-29a and miR-155 was an effective biomarker for distinguishing multiple myeloma from healthy donor, their sensitivity and specificity were 80.8% and 83.3% respectively for myeloma diagnosis. the change of miR-29a expression was consistent with the changes of bone marrow plasma cells and M protein levels. CONCLUSION: These circulating serum microRNA, such as miR-29a, miR-155 and miR-16, may serve as potential diagnostic biomarkers for multiple myeloma, and the ratio of miR-29a/miR-155 may serve as a most useful biomarker for myeloma diagnosis.

[Effect of Hedgehog Signaling Pathway Abnormality on Chemothe-rapeutic Resistance of Multiple Myeloma].

OBJECTIVE: To study the correlation between the excessive activation of Hedgehog signal and the drug resistance of multiple myeloma. METHODS: The resistant cell line RPMI 8226/R of multiple myeloma was established by an ascending concentration gradient method. The experiment consisted of 4 groups: RPMI8226/R, RPMI8226/S, GANT61+RPMI8226/R and GANT61+RPMI8226/S. The CCK-8 (cell counting kit-8) assay was used to detect the cell proliferation inhibition rate in 4 groups; the RT-PCR was used to detect the expression of Gli1, Gli2, Shh, Ihh, Smo and Sufu in the RPMI8226/S and RPMI8226/R cells. The Western blot was used to detect the expression of the resistant protein Cyclin D1, P21 and BCL-2 and MDR-related signaling pathways protein p-Akt, p-MAPK and STAT3 in the RPMI8226/S and RPMI8226/R cells. After adding different concentration of GANT61, the Western blot was used to detect the expression of Gli2 in RPMI8226/R and RPMI8226/S cells. RESULTS: The expression of Shh, Ihh, Smo Gli2 was enhanced significantly in the RPMI8226/R cells, but the expression of Sufu inhibitor was reduced, the expression level of related protein in Hedgehog signaling pathway was significanly higher in RPMI8226/R than that in RPMI8226/S. After theatment of GANT61 in vitro, the expression level of Gli2 in multiple myelom cells obviously decreased, the decreasing effect of GANT61 on Gli2 expression in RPMI8226/R cells was more significant than that in RPMI8226/S cells. The sensitivity of RPMI8226/R cells to DOX after treatment with GANT61 (IC50) was risen from 7.11±0.061 µmol/L to 0.99±0.053 µmol/L, the corresponding cell resistance index decreased from 5.51 to 1.69. CONCLUSION: the activation of Hedgehog signaling pathway is closely related with the resistance of multiple myeloma cells, and GANT61 can block the Hedgehog signaling pathway, thus Hedgehog signaling may be used as a new target for multiple myeloma treatment.

[Research Progress on the Drug Resistance Mechanism of Acute Myeloid Leukemia Mediated by the MicroRNA -Review].

The acute myeloid leukemia is a very common malignant tumor of hematopoietic system, which is seriously harmful to human health. The long-term survival rate of routine chemotherapy is not satisfactory, especially in the high risk patients. Resistance to chemotherapy drugs is one of the major reasons, which causes the refractorines and relapse of the acute myeloid leukemia. The microRNA found in eukaryote is an endogenous non-coding micromolecular signle-stranded RNA of 19 to 25 nt. The miRNA can degrade the specific RNA or inhibit its translation through combining to 3' untranslated regions of the specific RNA, which contributes to regulate the expression of the target gene. There are already some evidences showing that the disorder of miRNA plays an important role in the genesis and progress of the tumors. Recently, more and more researches suggest that the miRNA is also important in the genesis of drug resistance to tumors. This review summarizes the research progress and the major mechanism of drug-resistance mediated by the miRNA in AML, including multiple drug resistance, cell cycle and the tolerance to apoptosis, all of which are associated with ABC transport protein.