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1.
Neural Netw ; 180: 106710, 2024 Sep 07.
Article in English | MEDLINE | ID: mdl-39270347

ABSTRACT

For current image caption tasks used to encode region features and grid features Transformer-based encoders have become commonplace, because of their multi-head self-attention mechanism, the encoder can better capture the relationship between different regions in the image and contextual information. However, stacking Transformer blocks necessitates quadratic computation through self-attention to visual features, not only resulting in the computation of numerous redundant features but also significantly increasing computational overhead. This paper presents a novel Distilled Cross-Combination Transformer (DCCT) network. Technically, we first introduce a distillation cascade fusion encoder (DCFE), where a probabilistic sparse self-attention layer is used to filter out some redundant and distracting features that affect attention focus, aiming to obtain more refined visual features and enhance encoding efficiency. Next, we develop a parallel cross-fusion attention module (PCFA) that fully exploits the complementarity and correlation between grid and region features to better fuse the encoded dual visual features. Extensive experiments conducted on the MSCOCO dataset demonstrate that our proposed DCCT method achieves outstanding performance, rivaling current state-of-the-art approaches.

2.
Cell Death Dis ; 15(8): 631, 2024 Aug 28.
Article in English | MEDLINE | ID: mdl-39198402

ABSTRACT

Angiogenesis is critical for colorectal cancer (CRC) progression, but its mechanisms remain unclear. Here, we reveal that ethylmalonic encephalopathy protein 1 (ETHE1), an essential enzyme in hydrogen sulfide catabolism, inhibits VEGF-A expression and tumor angiogenesis in vitro and in vivo. Moreover, we find that this biological function of ETHE1 depends on the STAT3/VEGF-A pathway. Further investigation demonstrates that ETHE1 promotes the interaction between T cell protein tyrosine phosphatase (TC45) and STAT3, resulting in decreased STAT3 phosphorylation and inhibition of the STAT3 signaling pathway. In clinical samples, we find that ETHE1 is downregulated in CRC and positively correlates with survival outcomes of CRC patients. Meanwhile, the negative correlation of ETHE1 and VEGF-A expression is verified in CRC specimens, and the patients with low ETHE1 and high VEGF-A expression exhibits poorer prognosis. Collectively, our study identifies ETHE1 as a novel regulator of tumor angiogenesis, implying its potential as a prognostic biomarker and promising antiangiogenic target for CRC patients.


Subject(s)
Colorectal Neoplasms , Neovascularization, Pathologic , STAT3 Transcription Factor , Vascular Endothelial Growth Factor A , Humans , STAT3 Transcription Factor/metabolism , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor A/genetics , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/blood supply , Neovascularization, Pathologic/metabolism , Neovascularization, Pathologic/genetics , Phosphorylation , Animals , Mice , Mice, Nude , Male , Cell Line, Tumor , Female , Gene Expression Regulation, Neoplastic , Signal Transduction , Mice, Inbred BALB C , Angiogenesis
3.
Mikrochim Acta ; 191(9): 561, 2024 08 24.
Article in English | MEDLINE | ID: mdl-39180707

ABSTRACT

A novel "turn-on" aptasensor for kanamycin (Kana) detection based on a new Förster resonance energy transfer (FRET) pair is reported. A new organic small molecule was employed as a high-efficiency quencher for fluorophore. Based on specific interactions between ssDNA and the quencher, an ingenious and amplified strategy was designed. In the absence of the target, the fluorescence of the fluorophore labeled at the end of the aptamer was quenched. After the binding of the aptamer to the target, the fluorescence was recovered and amplified. The proposed aptasensor showed high specificity, selectivity, and stability in complicated systems. With the P3-based strategy, the limit of detection for Kana is estimated to be 10 nM, which is much lower than the maximum allowable concentration in milk. The recoveries of spiked Kana in milk were in the range 99.8 ~ 105.3% (n = 3). Fortunately, this novel method can be easily extended to other antibiotics such as tobramycin by simply replacing the aptamer, showing great potential as a universal platform for selective, sensitive, and rapid detection of hazardous analytes in food samples.


Subject(s)
Anti-Bacterial Agents , Aptamers, Nucleotide , Biosensing Techniques , Fluorescence Resonance Energy Transfer , Fluorescent Dyes , Kanamycin , Limit of Detection , Milk , Aptamers, Nucleotide/chemistry , Fluorescence Resonance Energy Transfer/methods , Anti-Bacterial Agents/analysis , Kanamycin/analysis , Milk/chemistry , Animals , Fluorescent Dyes/chemistry , Biosensing Techniques/methods , Food Contamination/analysis , DNA, Single-Stranded/chemistry
4.
J Med Virol ; 96(5): e29521, 2024 May.
Article in English | MEDLINE | ID: mdl-38727013

ABSTRACT

Methylation panels, tools for investigating epigenetic changes associated with diseases like cancer, can identify DNA methylation patterns indicative of disease, providing diagnostic or prognostic insights. However, the application of methylation panels focusing on the sex-determining region Y-box 1 (SOX1) and paired box gene 1 (PAX1) genes for diagnosing cervical lesions is under-researched. This study aims to examine the diagnostic performance of PAX1/SOX1 gene methylation as a marker for cervical precancerous lesions and its potential application in triage diagnosis. From September 2022 to April 2023, 181 patients with abnormal HPV-DNA tests or cytological exam results requiring colposcopy were studied at Hubei Maternal and Child Health Hospital, China. Data were collected from colposcopy, cytology, HPV-DNA tests, and PAX1/SOX1 methylation detection. Patients were categorized as control, cervical intraepithelial neoplasia Grade 1 (CIN1), Grade 2 (CIN2), Grade 3 (CIN3), and cervical cancer (CC) groups based on histopathology. We performed HPV testing, liquid-based cytology, and PAX1/SOX1 gene methylation testing. We evaluated the diagnostic value of methylation detection in cervical cancer using DNA methylation positivity rate, sensitivity, specificity, and area under the curve (AUC), and explored its potential for triage diagnosis. PAX1/SOX1 methylation positivity rates were: control 17.1%, CIN1 22.5%, CIN2 100.0%, CIN3 90.0%, and CC 100.0%. The AUC values for PAX1 gene methylation detection in diagnosing CIN1+, CIN2+, and CIN3+ were 0.52 (95% confidence interval [CI]: 0.43-0.62), 0.88 (95% CI: 0.80-0.97), and 0.88 (95% CI: 0.75-1.00), respectively. Corresponding AUC values for SOX1 gene methylation detection were 0.47 (95% CI: 0.40-0.58), 0.80 (95% CI: 0.68-0.93), and 0.92 (95% CI: 0.811-1.00), respectively. In HPV16/18-negative patients, methylation detection showed sensitivity of 32.4% and specificity of 83.7% for CIN1+. For CIN2+ and CIN3+, sensitivity was all 100%, with specificities of 83.0% and 81.1%. Among the patients who underwent colposcopy examination, 166 cases had cytological examination results ≤ASCUS, of which 37 cases were positive for methylation, and the colposcopy referral rate was 22.29%. PAX1/SOX1 gene methylation detection exhibits strong diagnostic efficacy for cervical precancerous lesions and holds significant value in triage diagnosis.


Subject(s)
DNA Methylation , Paired Box Transcription Factors , Papillomavirus Infections , SOXB1 Transcription Factors , Uterine Cervical Dysplasia , Uterine Cervical Neoplasms , Adult , Female , Humans , Middle Aged , Young Adult , Biomarkers, Tumor/genetics , China , Colposcopy , Early Detection of Cancer/methods , Paired Box Transcription Factors/genetics , Papillomavirus Infections/diagnosis , Papillomavirus Infections/virology , Papillomavirus Infections/genetics , Precancerous Conditions/diagnosis , Precancerous Conditions/genetics , Sensitivity and Specificity , SOXB1 Transcription Factors/genetics , Triage/methods , Uterine Cervical Dysplasia/diagnosis , Uterine Cervical Dysplasia/genetics , Uterine Cervical Dysplasia/virology , Uterine Cervical Neoplasms/diagnosis , Uterine Cervical Neoplasms/genetics
5.
Br J Surg ; 111(5)2024 May 03.
Article in English | MEDLINE | ID: mdl-38713611

ABSTRACT

BACKGROUND: It is unknown whether D2 lymphadenectomy + complete mesogastric excision for gastric cancer improves survival compared with just D2 lymphadenectomy. METHODS: Between September 2014 and June 2018, patients with advanced gastric cancer were randomly assigned (1 : 1) to laparoscopic D2 lymphadenectomy or D2 lymphadenectomy + complete mesogastric excision gastrectomy. The modified intention-to-treat population was defined as patients who had pathologically confirmed gastric adenocarcinoma (pT1 N1-3 M0 and pT2-4 N0-3 M0). The primary endpoint was 3-year disease-free survival. Secondary endpoints were the recurrence pattern and overall survival. RESULTS: The median follow-up of patients in the D2 lymphadenectomy group (169 patients) and patients in the D2 lymphadenectomy +complete mesogastric excision group (169 patients) was 55 (interquartile range 37-60) months and 51 (interquartile range 40-60) months respectively. Recurrence occurred in 50 patients in the D2 lymphadenectomy group (29.6%) versus 33 patients in the D2 lymphadenectomy + complete mesogastric excision group (19.5%) (P = 0.032). The 3-year disease-free survival was 75.5% (95% c.i. 68.3% to 81.3%) in the D2 lymphadenectomy group versus 85.0% (95% c.i. 78.7% to 89.6%) in the D2 lymphadenectomy + complete mesogastric excision group (log rank P = 0.042). The HR for recurrence in the D2 lymphadenectomy + complete mesogastric excision group versus the D2 lymphadenectomy group was 0.64 (95% c.i. 0.41 to 0.99) by Cox regression (P = 0.045). The 3-year overall survival rate was 77.5% (95% c.i. 70.4% to 83.1%) in the D2 lymphadenectomy group versus 85.8% (95% c.i. 79.6% to 90.2%) in the D2 lymphadenectomy + complete mesogastric excision group (log rank P = 0.058). The HR for death in the D2 lymphadenectomy + complete mesogastric excision group versus the D2 lymphadenectomy group was 0.64 (95% c.i. 0.41 to 1.02) (P = 0.058). CONCLUSION: Compared with conventional D2 dissection, D2 lymphadenectomy + complete mesogastric excision is associated with better disease-free survival, but there is no statistically significant difference in overall survival. REGISTRATION NUMBER: NCT01978444 (http://www.clinicaltrials.gov).


Subject(s)
Adenocarcinoma , Gastrectomy , Lymph Node Excision , Stomach Neoplasms , Humans , Stomach Neoplasms/surgery , Stomach Neoplasms/pathology , Stomach Neoplasms/mortality , Gastrectomy/methods , Lymph Node Excision/methods , Male , Female , Middle Aged , Adenocarcinoma/surgery , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Aged , Laparoscopy/methods , Disease-Free Survival , Neoplasm Recurrence, Local , Adult , Survival Rate , Neoplasm Staging
6.
Oncogene ; 43(21): 1581-1593, 2024 May.
Article in English | MEDLINE | ID: mdl-38565942

ABSTRACT

Deubiquitinating enzymes (DUBs) are promising targets for cancer therapy because of their pivotal roles in various physiological and pathological processes. Among these, ubiquitin-specific peptidase 26 (USP26) is a protease with crucial regulatory functions. Our study sheds light on the upregulation of USP26 in colorectal cancer (CRC), in which its increased expression correlates with an unfavorable prognosis. Herein, we evidenced the role of USP26 in promoting CRC tumorigenesis in a parkin RBR E3 ubiquitin-protein ligase (PRKN) protein-dependent manner. Our investigation revealed that USP26 directly interacted with PRKN protein, facilitating its deubiquitination, and subsequently reducing its activity. Additionally, we identified the K129 site on PRKN as a specific target for USP26-mediated deubiquitination. Our research highlights that a K-to-R mutation at the site on PRKN diminishes its potential for activation and ability to mediate mitophagy. In summary, our findings underscore the significance of USP26-mediated deubiquitination in restraining the activation of the PRKN-mediated mitophagy pathway, ultimately driving CRC tumorigenesis. This study not only elucidated the multifaceted role of USP26 in CRC but also introduced a promising avenue for therapeutic exploration through the development of small molecule inhibitors targeting USP26. This strategy holds promise as a novel therapeutic approach for CRC.


Subject(s)
Carcinogenesis , Colorectal Neoplasms , Mitophagy , Ubiquitin-Protein Ligases , Ubiquitination , Colorectal Neoplasms/pathology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Humans , Mitophagy/genetics , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/genetics , Animals , Carcinogenesis/genetics , Carcinogenesis/metabolism , Mice , Cell Line, Tumor , Cysteine Endopeptidases/metabolism , Cysteine Endopeptidases/genetics , Mice, Nude , Gene Expression Regulation, Neoplastic
7.
PLoS One ; 19(1): e0297525, 2024.
Article in English | MEDLINE | ID: mdl-38277398

ABSTRACT

Notch pathway has played a significant role in the pathophysiology of pulmonary hypertension (PH). However, the role of Jagged 2 (Jag2), one ligand of Notch, remains to be elucidated.Therefore, determining the contribution of Jag2 to PH and its impact on pulmonary artery smooth muscle cells (PASMCs) was the aim of this investigation. Adeno-associated virus-mediated Jag2 inhibition was used to explore the role of Jag2 in peripheral pulmonary vascular remodeling assessed in a rat model of chronic hypoxia (10% O2, 4 weeks) induced pulmonary hypertension. In vitro, the effect of Jag2 silencing on hypoxia (1% O2, 24h) induced rat PASMCs was determined. Group differences were assessed using a 2-sided unpaired Student's t-test for two groups and one-way ANOVA for multiple groups. Jag2 upregulation was first confirmed in rats with sustained hypoxia-induced PH using publicly available gene expression data, experimental PH rat models and hypoxia induced rat PASMCs. Jag2 deficiency decreased oxidative stress injury, peripheral pulmonary vascular remodeling (0.276±0.020 vs. 0.451±0.033 µm, P<0.001, <50µm), and right ventricular systolic pressure (36.8±3.033 vs. 51.8±4.245 mmHg, P<0.001) in the chronic hypoxia-induced rat model of PH. Moreover, Jag2 knockdown decreased proliferation (1.227±0.051 vs. 1.45±0.07, P = 0.012), increased apoptosis (16.733%±0.724% vs. 6.56%±0.668%, P<0.001), and suppressed mitochondrial injury in hypoxia-treated rat PASMCs. Jag2 inhibition restored the activity of the Nrf2/HO-1 pathway, which was abolished by Sirtuin 1 deficiency. These findings show that Jag2 is essential for modulating pulmonary vascular dysfunction and accelerating PH, and that inhibition of Jag2 expression suppresses the progression and development of PH.


Subject(s)
Hypertension, Pulmonary , Animals , Rats , Cell Proliferation/physiology , Cells, Cultured , Hypertension, Pulmonary/metabolism , Hypoxia/metabolism , Myocytes, Smooth Muscle/metabolism , Pulmonary Artery , Sirtuin 1/metabolism , Vascular Remodeling
8.
Analyst ; 149(2): 290-303, 2024 Jan 15.
Article in English | MEDLINE | ID: mdl-38099470

ABSTRACT

Telomerase as a new valuable biomarker for early diagnosis and prognosis evaluation of cancer has attracted much interest in the field of biosensors, cell imaging, and drug screening. In this review, we mainly focus on different optical techniques and various signal amplification strategies for telomerase activity determination. Fluorometric, colorimetry, chemiluminescence, surface-enhanced Raman scattering (SERS), and dual-mode techniques for telomerase sensing and imaging are summarized. Signal amplification strategies include two categories: one is nucleic acid-based amplification, such as rolling circle amplification (RCA), the hybridization chain reaction (HCR), and catalytic hairpin assembly (CHA); the other is nanomaterial-assisted amplification, including metal nanoclusters, quantum dots, transition metal compounds, graphene oxide, and DNA nanomaterials. Challenges and prospects are also discussed to provide new insights for future development of multifunctional strategies and techniques for in situ and in vivo analysis of biomarkers for accurate cancer diagnosis.


Subject(s)
Biosensing Techniques , Neoplasms , Telomerase , Humans , Telomerase/analysis , DNA/analysis , Nucleic Acid Hybridization/methods , Diagnostic Imaging , Biosensing Techniques/methods , Neoplasms/diagnostic imaging , Nucleic Acid Amplification Techniques/methods
9.
Proc Natl Acad Sci U S A ; 120(52): e2305684120, 2023 Dec 26.
Article in English | MEDLINE | ID: mdl-38113258

ABSTRACT

Metastasis is a major cause of cancer therapy failure and mortality. However, targeting metastatic seeding and colonization remains a significant challenge. In this study, we identified NSD2, a histone methyltransferase responsible for dimethylating histone 3 at lysine 36, as being overexpressed in metastatic tumors. Our findings suggest that NSD2 overexpression enhances tumor metastasis both in vitro and in vivo. Further analysis revealed that NSD2 promotes tumor metastasis by activating Rac1 signaling. Mechanistically, NSD2 combines with and activates Tiam1 (T lymphoma invasion and metastasis 1) and promotes Rac1 signaling by methylating Tiam1 at K724. In vivo and in vitro studies revealed that Tiam1 K724 methylation could be a predictive factor for cancer prognosis and a potential target for metastasis inhibition. Furthermore, we have developed inhibitory peptide which was proved to inhibit tumor metastasis through blocking the interaction between NSD2 and Tiam1. Our results demonstrate that NSD2-methylated Tiam1 promotes Rac1 signaling and cancer metastasis. These results provide insights into the inhibition of tumor metastasis.


Subject(s)
Colonic Neoplasms , Guanine Nucleotide Exchange Factors , Humans , Guanine Nucleotide Exchange Factors/genetics , Guanine Nucleotide Exchange Factors/metabolism , Signal Transduction/physiology , Neoplasm Invasiveness/pathology , Methylation , rac1 GTP-Binding Protein/genetics , rac1 GTP-Binding Protein/metabolism
10.
J Cancer Res Clin Oncol ; 149(20): 17973-17986, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37966613

ABSTRACT

PURPOSE: HPV integration usually occurs in HPV-related cancer, and is the main cause of cancer. But the carcinogenic mechanism of HPV integration is unclear. The study aims to provide a theoretical basis for understanding the pathogenesis of cervical adenocarcinoma (AC) and cervical squamous carcinoma (SCC). METHODS: We used HPV capture sequencing to obtain HPV integration sites in AC and SCC, and analyzed cytobands, distribution of genetic and genomic elements, identified integration hotspot genes, clinicopathological parameters, breakpoints of HPV16 and performed pathway analysis. Then we conducted immunohistochemical (IHC) assay to preliminarily verify the expression of most frequently integrated genes in AC, STARD3 and ERBB2. RESULTS: The results revealed that the most frequently observed integrated cytoband was 17q12 in AC and 21p11.2 in SCC, respectively. The breakpoints in both AC and SCC were more tended to occur within gene regions, compared to intergenetic regions. Compared to SCC samples, AC samples had a higher prevalence of genomic elements. In AC, HPV integration has no significantly difference with clinicopathological parameters, but in SCC integration correlated with differentiation (P < 0.05). Breakpoints of HPV in SCC located in LCR more frequently compared to AC, which destroyed the activation of promoter p97. Hotspot genes of HPV integration were STARD3 and ERBB2 in AC, and RNA45S rDNA and MIR3648-1 in SCC, respectively. Meanwhile, we preliminarily proved that the expression of STARD3 and ERBB2, the most frequently integrated genes, would increase after integration. CONCLUSION: These results suggested that HPV may utilize the powerful hosts' promoters to express viral oncogenes and overexpression of viral oncogenes plays a significant role in the carcinogenesis of SCC. In AC, HPV integration may affect hosts' oncogenes, and the dysregulation of oncogenes may primarily contribute to progression of AC.


Subject(s)
Adenocarcinoma , Carcinoma, Squamous Cell , Papillomavirus Infections , Uterine Cervical Neoplasms , Female , Humans , Papillomavirus Infections/complications , Papillomavirus Infections/genetics , Papillomavirus Infections/epidemiology , Human papillomavirus 16 , Adenocarcinoma/genetics , Papillomaviridae/genetics
11.
Adv Sci (Weinh) ; 10(36): e2303484, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37946697

ABSTRACT

Ferroptosis, which is caused by iron-dependent accumulation of lipid peroxides, is an emerging form of regulated cell death and is considered a potential target for cancer therapy. However, the regulatory mechanisms underlying ferroptosis remain unclear. This study defines a distinctive role of ferroptosis. Inhibition of CARM1 can increase the sensitivity of tumor cells to ferroptosis inducers in vitro and in vivo. Mechanistically, it is found that ACSL4 is methylated by CARM1 at arginine 339 (R339). Furthermore, ACSL4 R339 methylation promotes RNF25 binding to ACSL4, which contributes to the ubiquitylation of ACSL4. The blockade of CARM1 facilitates ferroptosis and effectively enhances ferroptosis-associated cancer immunotherapy. Overall, this study demonstrates that CARM1 is a critical contributor to ferroptosis resistance and highlights CARM1 as a candidate therapeutic target for improving the effects of ferroptosis-based antitumor therapy.


Subject(s)
Colorectal Neoplasms , Ferroptosis , Humans , Methylation , Protein-Arginine N-Methyltransferases/genetics , Colorectal Neoplasms/genetics
12.
Analyst ; 148(23): 5856-5863, 2023 Nov 20.
Article in English | MEDLINE | ID: mdl-37885382

ABSTRACT

A simple but robust fluorescence strategy based on a nontarget DNA-triggered catalytic hairpin assembly (CHA) was constructed to probe microRNA-21 (miR-21). A short ssDNA rather than degradable target miRNA was employed as an initiator. Two molecular beacons needed to assist the CHA process were simplified to avoid unfavorable nonspecific interactions. In the presence of the target, the initiator was released from a partially duplex and triggered the cyclic CHA reaction, resulting in a significantly amplified optical readout. A wide linear range from 0.1 pM to 1000 pM for the sensing of miR-21 in buffer was achieved with a low detection limit of 0.76 pM. Fortunately, this strategy demonstrated an obviously improved performance for miR-21 detection in diluted serum. The fluorescence signals were enhanced remarkably and the sensitivity was further improved to 0.12 pM in 10% serum. The stability for miR-21 quantification and the capability for the analysis of single nucleotide polymorphisms (SNPs) were also improved greatly. More importantly, the biosensor could be applied to image miR-21 in different living tumor cells with high resolution, illustrating its promising potential for the assay of miRNAs in various complex situations for early-stage disease diagnosis and biological studies in cells.


Subject(s)
Biological Assay , MicroRNAs , Catalysis , DNA, Single-Stranded/genetics , MicroRNAs/genetics , Polymorphism, Single Nucleotide
13.
Int J Clin Exp Pathol ; 16(9): 252-258, 2023.
Article in English | MEDLINE | ID: mdl-37818386

ABSTRACT

Uterine sarcomas are a group of rare malignant tumors of mesenchymal tissue of the uterus, and their diagnosis is often difficult because they have variable morphologies and no typical immunophenotype. This report describes a 48-year-old woman who underwent laparoscopic myomectomy and relapsed within 5 years with a large mass in the pelvic cavity. Morphologically, the tumor was composed of oval cells and small arteries, and the cells showed moderate to severe atypia. Immunohistochemical results showed that the tumor cells expressed desmin, smooth muscle actin, and h-caldesmon, which supported myogenic differentiation. They were strongly positive for Cyclin D1, estrogen receptors (ER), and estrogen receptors (PR), supporting their origin from uterine mesenchymal cells. Next-generation sequencing (NGS) revealed a GATAD2B::MMRN1 rearrangement. The patient was diagnosed with uterine sarcoma resembling high-grade endometrial mesenchymal sarcoma with a GATAD2B-MMRN1 fusion. We review the relevant literature and discuss the diagnostic and differential diagnostic points for this disease.

14.
Cell Rep ; 42(10): 113126, 2023 10 31.
Article in English | MEDLINE | ID: mdl-37756162

ABSTRACT

Fatty acid metabolism plays a critical role in both tumorigenesis and cancer radiotherapy. However, the regulatory mechanism of fatty acid metabolism has not been fully elucidated. NSD2, a histone methyltransferase that catalyzes di-methylation of histone H3 at lysine 36, has been shown to play an essential role in tumorigenesis and cancer progression. Here, we show that NSD2 promotes fatty acid oxidation (FAO) by methylating AROS (active regulator of SIRT1) at lysine 27, facilitating the physical interaction between AROS and SIRT1. The mutation of lysine 27 to arginine weakens the interaction between AROS and SIRT1 and impairs AROS-SIRT1-mediated FAO. Additionally, we examine the effect of NSD2 inhibition on radiotherapy efficacy and find an enhanced effectiveness of radiotherapy. Together, our findings identify a NSD2-dependent methylation regulation pattern of the AROS-SIRT1 axis, suggesting that NSD2 inhibition may be a potential adjunct for tumor radiotherapy.


Subject(s)
Neoplasms , Sirtuin 1 , Humans , Sirtuin 1/genetics , Repressor Proteins/metabolism , Lysine/metabolism , Histone-Lysine N-Methyltransferase/genetics , Histone-Lysine N-Methyltransferase/metabolism , Neoplasms/genetics , Neoplasms/radiotherapy , Carcinogenesis , Fatty Acids
15.
Adv Sci (Weinh) ; 10(28): e2301871, 2023 10.
Article in English | MEDLINE | ID: mdl-37541664

ABSTRACT

MCT1 is a critical protein found in monocarboxylate transporters that plays a significant role in regulating the lactate shuttle. However, the post-transcriptional modifications that regulate MCT1 are not clearly identified. In this study, it is reported that SETDB1 interacts with MCT1, leading to its stabilization. These findings reveal a novel post-translational modification of MCT1, in which SETDB1 methylation occurs at K473 in vitro and in vivo. This methylation inhibits the interaction between MCT1 and Tollip, which blocks Tollip-mediated autophagic degradation of MCT1. Furthermore, MCT1 K473 tri-methylation promotes tumor glycolysis and M2-like polarization of tumor-associated macrophages in colorectal cancer (CRC), which enhances the lactate shuttle. In clinical studies, MCT1 K473 tri-methylation is found to be upregulated and positively correlated with tumor progression and overall survival in CRC. This discovery suggests that SETDB1-mediated tri-methylation at K473 is a vital regulatory mechanism for lactate shuttle and tumor progression. Additionally, MCT1 K473 methylation may be a potential prognostic biomarker and promising therapeutic target for CRC.


Subject(s)
Neoplasms , Symporters , Humans , Lactic Acid/metabolism , Histone-Lysine N-Methyltransferase/metabolism
16.
Medicine (Baltimore) ; 102(19): e33801, 2023 May 12.
Article in English | MEDLINE | ID: mdl-37171299

ABSTRACT

RATIONALE: Anastomosing hemangioma (AH) is a rare benign neoplastic vascular lesion that histologically resembles a well-differentiated angiosarcoma. AH commonly involves the urinary system and testes. However, these tumors can also involve the ovaries in some rare cases. This manuscript presents the case of a 28-year-old Chinese woman diagnosed with ovarian AH. PATIENT CONCERNS: The woman was admitted to the hospital with a 4-month history of a right ovarian mass discovered by ultrasound (US) after a spontaneous abortion. The US examination showed a 4 cm × 4 cm irregularly shaped mass with a rich blood supply. DIAGNOSES: AH of the right ovar. INTERVENTION: The patient underwent laparoscopic surgery to remove the mass. The postoperative pathological examination revealed that the mass contained capillaries arranged in a characteristic anastomotic or confluent pattern commonly seen in AHs. OUTCOMES: The mass was successfully removed. The follow-up examination at 7 months post-surgery showed that the patient recovered well, and no recurrence or metastasis was found. LESSONS: AH of the ovary is a rare benign vascular tumor. On imaging examinations, AHs appear as mostly well-defined, heterogeneous nodules with peripheral enhancement as other benign nodules. However, a definitive diagnosis can only be achieved through histopathological examination.


Subject(s)
Hemangioma , Hemangiosarcoma , Vascular Neoplasms , Female , Humans , Adult , Ovary/diagnostic imaging , Ovary/surgery , Ovary/pathology , Hemangioma/diagnostic imaging , Hemangioma/surgery , Hemangiosarcoma/pathology , Vascular Neoplasms/diagnosis , Diagnosis, Differential
17.
Sci Adv ; 9(21): eade4186, 2023 05 26.
Article in English | MEDLINE | ID: mdl-37235656

ABSTRACT

Immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) or programmed cell death 1 ligand 1 (PD-L1) have enabled some patients with cancer to experience durable, complete treatment responses; however, reliable anti-PD-(L)1 treatment response biomarkers are lacking. Our research found that PD-L1 K162 was methylated by SETD7 and demethylated by LSD2. Furthermore, PD-L1 K162 methylation controlled the PD-1/PD-L1 interaction and obviously enhanced the suppression of T cell activity controlling cancer immune surveillance. We demonstrated that PD-L1 hypermethylation was the key mechanism for anti-PD-L1 therapy resistance, investigated that PD-L1 K162 methylation was a negative predictive marker for anti-PD-1 treatment in patients with non-small cell lung cancer, and showed that the PD-L1 K162 methylation:PD-L1 ratio was a more accurate biomarker for predicting anti-PD-(L)1 therapy sensitivity. These findings provide insights into the regulation of the PD-1/PD-L1 pathway, identify a modification of this critical immune checkpoint, and highlight a predictive biomarker of the response to PD-1/PD-L1 blockade therapy.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , B7-H1 Antigen , Methylation , Biomarkers , Histone-Lysine N-Methyltransferase
18.
Oncogene ; 42(19): 1572-1584, 2023 05.
Article in English | MEDLINE | ID: mdl-36991117

ABSTRACT

Perturbations in transforming growth factor-ß (TGF-ß) signaling can lead to a plethora of diseases, including cancer. Mutations and posttranslational modifications (PTMs) of the partner of SMAD complexes contribute to the dysregulation of TGF-ß signaling. Here, we reported a PTM of SMAD4, R361 methylation, that was critical for SMAD complexes formation and TGF-ß signaling activation. Through mass spectrometric, co-immunoprecipitation (Co-IP) and immunofluorescent (IF) assays, we found that oncogene protein arginine methyltransferase 5 (PRMT5) interacted with SMAD4 under TGF-ß1 treatment. Mechanically, PRMT5 triggered SMAD4 methylation at R361 and induced SMAD complexes formation and nuclear import. Furthermore, we emphasized that PRMT5 interacting and methylating SMAD4 was required for TGF-ß1-induced epithelial-mesenchymal transition (EMT) and colorectal cancer (CRC) metastasis, and SMAD4 R361 mutation diminished PRMT5 and TGF-ß1-induced metastasis. In addition, highly expressed PRMT5 or high level of SMAD4 R361 methylation indicated worse outcomes in clinical specimens analysis. Collectively, our study highlights the critical interaction of PRMT5 and SMAD4 and the roles of SMAD4 R361 methylation for controlling TGF-ß signaling during metastasis. We provided a new insight for SMAD4 activation. And this study indicated that blocking PRMT5-SMAD4 signaling might be an effective targeting strategy in SMAD4 wild-type CRC.


Subject(s)
Colorectal Neoplasms , Protein-Arginine N-Methyltransferases , Smad4 Protein , Transforming Growth Factor beta , Humans , Cell Line, Tumor , Colorectal Neoplasms/pathology , Protein-Arginine N-Methyltransferases/genetics , Protein-Arginine N-Methyltransferases/metabolism , Signal Transduction , Smad4 Protein/genetics , Smad4 Protein/metabolism , Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta1/metabolism , Neoplasm Metastasis
19.
Oncogene ; 41(25): 3433-3444, 2022 06.
Article in English | MEDLINE | ID: mdl-35589951

ABSTRACT

RIO Kinase 1 (RIOK1) is involved in various pathologies, including cancer. However, the role of RIOK1 in radioresistance of colorectal cancer (CRC) remains largely unknown. In this study, we reported that RIOK1 was overexpressed in rectal cancer tissue with weaker tumor regression after neoadjuvant chemoradiotherapy (neoCRT). Moreover, higher RIOK1 expression predicted a poor prognosis in patients with rectal cancer. Blockade of RIOK1 using Toyocamycin, a pharmacological inhibitor of RIOK1, or by knocking down its expression, decreased the resistance of CRC cells to radiotherapy in vitro and in vivo. A mechanistic study revealed that RIOK1 regulates radioresistance by suppressing the p53 signaling pathway. Furthermore, we found that RIOK1 and Ras-GAP SH3 domain binding protein 2 (G3BP2) interact with each other. RIOK1 phosphorylates G3BP2 at Thr226, which increases the activity of G3BP2. RIOK1-mediated phosphorylation of G3BP2 facilitated ubiquitination of p53 by murine double minute 2 protein (MDM2). Altogether, our study revealed the clinical significance of RIOK1 in CRC, and therapies targeting RIOK1 might alleviate the CRC tumor burden in patients.


Subject(s)
Colorectal Neoplasms , Protein Serine-Threonine Kinases/metabolism , Rectal Neoplasms , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Animals , Cell Line, Tumor , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/radiotherapy , Humans , Mice , Phosphorylation , Proto-Oncogene Proteins c-mdm2/metabolism , RNA-Binding Proteins/metabolism , Tumor Suppressor Protein p53/metabolism
20.
J Clin Invest ; 132(5)2022 03 01.
Article in English | MEDLINE | ID: mdl-35085106

ABSTRACT

SMAD3 plays a central role in cancer metastasis, and its hyperactivation is linked to poor cancer outcomes. Thus, it is critical to understand the upstream signaling pathways that govern SMAD3 activation. Here, we report that SMAD3 underwent methylation at K53 and K333 (K53/K333) by EZH2, a process crucial for cell membrane recruitment, phosphorylation, and activation of SMAD3 upon TGFB1 stimulation. Mechanistically, EZH2-triggered SMAD3 methylation facilitated SMAD3 interaction with its cellular membrane localization molecule (SARA), which in turn sustained SMAD3 phosphorylation by the TGFB receptor. Pathologically, increased expression of EZH2 expression resulted in the accumulation of SMAD3 methylation to facilitate SMAD3 activation. EZH2-mediated SMAD3 K53/K333 methylation was upregulated and correlated with SMAD3 hyperactivation in breast cancer, promoted tumor metastasis, and was predictive of poor survival outcomes. We used 2 TAT peptides to abrogate SMAD3 methylation and therapeutically inhibit cancer metastasis. Collectively, these findings reveal the complicated layers involved in the regulation of SMAD3 activation coordinated by EZH2-mediated SMAD3 K53/K333 methylation to drive cancer metastasis.


Subject(s)
Breast Neoplasms , Smad3 Protein , Breast Neoplasms/pathology , Cell Line, Tumor , Enhancer of Zeste Homolog 2 Protein/genetics , Enhancer of Zeste Homolog 2 Protein/metabolism , Female , Gene Expression Regulation, Neoplastic , Humans , Methylation , Phosphorylation , Signal Transduction , Smad3 Protein/genetics , Smad3 Protein/metabolism
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