RESUMO
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.
Assuntos
Metilação de DNA , Fatores de Transcrição Box Pareados , Infecções por Papillomavirus , Fatores de Transcrição SOXB1 , Displasia do Colo do Útero , Neoplasias do Colo do Útero , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Biomarcadores Tumorais/genética , China , Colposcopia , Detecção Precoce de Câncer/métodos , Fatores de Transcrição Box Pareados/genética , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/genética , Lesões Pré-Cancerosas/diagnóstico , Lesões Pré-Cancerosas/genética , Sensibilidade e Especificidade , Fatores de Transcrição SOXB1/genética , Triagem/métodos , Displasia do Colo do Útero/diagnóstico , Displasia do Colo do Útero/genética , Displasia do Colo do Útero/virologia , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/genéticaRESUMO
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)â months and 51 (interquartile range 40-60)â 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).
Assuntos
Adenocarcinoma , Gastrectomia , Excisão de Linfonodo , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/cirurgia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/mortalidade , Gastrectomia/métodos , Excisão de Linfonodo/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Adenocarcinoma/cirurgia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Idoso , Laparoscopia/métodos , Intervalo Livre de Doença , Recidiva Local de Neoplasia , Adulto , Taxa de Sobrevida , Estadiamento de NeoplasiasRESUMO
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.
Assuntos
Carcinogênese , Neoplasias Colorretais , Mitofagia , Ubiquitina-Proteína Ligases , Ubiquitinação , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Humanos , Mitofagia/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Camundongos , Linhagem Celular Tumoral , Cisteína Endopeptidases/metabolismo , Cisteína Endopeptidases/genética , Camundongos Nus , Regulação Neoplásica da Expressão GênicaRESUMO
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.
Assuntos
Hipertensão Pulmonar , Animais , Ratos , Proliferação de Células/fisiologia , Células Cultivadas , Hipertensão Pulmonar/metabolismo , Hipóxia/metabolismo , Miócitos de Músculo Liso/metabolismo , Artéria Pulmonar , Sirtuína 1/metabolismo , Remodelação VascularRESUMO
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.
Assuntos
Técnicas Biossensoriais , Neoplasias , Telomerase , Humanos , Telomerase/análise , DNA/análise , Hibridização de Ácido Nucleico/métodos , Diagnóstico por Imagem , Técnicas Biossensoriais/métodos , Neoplasias/diagnóstico por imagem , Técnicas de Amplificação de Ácido Nucleico/métodosRESUMO
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.
Assuntos
Neoplasias do Colo , Fatores de Troca do Nucleotídeo Guanina , Humanos , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Transdução de Sinais/fisiologia , Invasividade Neoplásica/patologia , Metilação , Proteínas rac1 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/metabolismoRESUMO
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.
Assuntos
Neoplasias Colorretais , Ferroptose , Humanos , Metilação , Proteína-Arginina N-Metiltransferases/genética , Neoplasias Colorretais/genéticaRESUMO
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.
Assuntos
Adenocarcinoma , Carcinoma de Células Escamosas , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Feminino , Humanos , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/epidemiologia , Papillomavirus Humano 16 , Adenocarcinoma/genética , Papillomaviridae/genéticaRESUMO
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.
RESUMO
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.
Assuntos
Bioensaio , MicroRNAs , Catálise , DNA de Cadeia Simples/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
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.
Assuntos
Neoplasias , Sirtuína 1 , Humanos , Sirtuína 1/genética , Proteínas Repressoras/metabolismo , Lisina/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Neoplasias/genética , Neoplasias/radioterapia , Carcinogênese , Ácidos GraxosRESUMO
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.
Assuntos
Neoplasias , Simportadores , Humanos , Ácido Láctico/metabolismo , Histona-Lisina N-Metiltransferase/metabolismoRESUMO
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.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Antígeno B7-H1 , Metilação , Biomarcadores , Histona-Lisina N-MetiltransferaseRESUMO
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.
Assuntos
Hemangioma , Hemangiossarcoma , Neoplasias Vasculares , Feminino , Humanos , Adulto , Ovário/diagnóstico por imagem , Ovário/cirurgia , Ovário/patologia , Hemangioma/diagnóstico por imagem , Hemangioma/cirurgia , Hemangiossarcoma/patologia , Neoplasias Vasculares/diagnóstico , Diagnóstico DiferencialRESUMO
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.
Assuntos
Neoplasias Colorretais , Proteína-Arginina N-Metiltransferases , Proteína Smad4 , Fator de Crescimento Transformador beta , Humanos , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Transdução de Sinais , Proteína Smad4/genética , Proteína Smad4/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Metástase NeoplásicaRESUMO
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.
Assuntos
Neoplasias Colorretais , Proteínas Serina-Treonina Quinases/metabolismo , Neoplasias Retais , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/radioterapia , Humanos , Camundongos , Fosforilação , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
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.
Assuntos
Neoplasias da Mama , Proteína Smad3 , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metilação , Fosforilação , Transdução de Sinais , Proteína Smad3/genética , Proteína Smad3/metabolismoRESUMO
BACKGROUND: The safety and feasibility of laparoscopic surgery for the management of rectal gastrointestinal stromal tumors are unknown. OBJECTIVE: This study aimed to compare the surgical and oncologic results of laparoscopic versus open surgery for the treatment of rectal gastrointestinal stromal tumors. DESIGN: This was a retrospective multicenter propensity score-matched study to minimize heterogeneity between groups and focus on the difference between surgery strategies. SETTINGS: Eleven Chinese tertiary hospitals participated in this study. PATIENTS: A total of 364 patients with pathologically confirmed rectal gastrointestinal stromal tumors were retrospectively analyzed. MAIN OUTCOME MEASURES: Relapse-free survival, postoperative hospital stay length, and 30-day postoperative complication rate were the main outcome measures. RESULTS: We enrolled 214 patients who underwent surgical operation for primary localized rectal gastrointestinal stromal tumors. After propensity score matching, 134 cases involved in the comparison (67 laparoscopic vs 67 open surgery) were randomly matched (1:1) by sex, age, tumor size, tumor site, and neoadjuvant therapy. The laparoscopic surgery group had superior relapse-free survival (χ2 = 4.46, p = 0.04), and fewer complications (6.0% vs 25.4%, p = 0.002). No significant difference was found in the length of postoperative hospital stay between the laparoscopic surgery and open surgery groups (9.66 ± 5.42 vs. 10.64 ± 4.93, p = 0.28). Subgroup analysis showed that the laparoscopic surgery group had superior relapse-free survival (χ2 = 4.14, p = 0.04) and fewer complications after surgery (2.9% vs 24.4%, p = 0.01) in the rectal gastrointestinal stromal tumors ≤5 cm subgroup. LIMITATIONS: This study was limited by the nature of retrospective reviews and relatively short follow-up period. CONCLUSIONS: Laparoscopic surgery offers a safe and feasible option for the radical resection of primary localized rectal gastrointestinal stromal tumors, especially for patients with rectal gastrointestinal stromal tumors ≤5 cm. See Video Abstract at http://links.lww.com/DCR/B764. CIRUGA LAPAROSCPICA VERSUS CIRUGA ABIERTA PARA TUMORES DEL ESTROMA GASTROINTESTINAL DE RECTO UN ANLISIS MULTICNTRICO EMPAREJADO POR PUNTAJE DE PROPENSIN: ANTECEDENTES:Se desconoce la seguridad y factibilidad de la cirugía laparoscópica para el tratamiento de los tumores del estroma gastrointestinal de recto.OBJETIVO:Comparar los resultados quirúrgicos y oncológicos de la cirugía laparoscópica versus cirugía abierta para el tratamiento de los tumores del estroma gastrointestinal de recto.DISEÑO:Estudio retrospectivo multicéntrico emparejado por puntuación de propensión para minimizar la heterogeneidad entre los grupos y centrarse en las diferencias entre las estrategias quirúrgicas.AJUSTES:Once hospitales terciarios de la China participaron en este estudio.PACIENTES:Se analizaron retrospectivamente un total de 364 pacientes con tumores del estroma gastrointestinal de recto confirmados patológicamente.PRINCIPALES MEDIDAS DE VALORACION:Supervivencia sin recidiva, duración de la estancia hospitalaria postquirúrgica y tasa de complicaciones postquirúrgicas a los 30 días.RESULTADOS:Inscribimos a 214 pacientes que fueron sometidos a cirugía por tumores primariamente localizados del estroma gastrointestinal de recto. Después del emparejamiento por puntaje de propensión, 134 casos involucrados en la comparación (67 laparoscópicos versus 67 cirugía abierta) fueron emparejados aleatoriamente (1: 1) por sexo, edad, tamaño del tumor, sitio del tumor y terapia neoadyuvante. El grupo de cirugía laparoscópica tuvo una supervivencia sin recidiva superior (χ2 = 4,46, p = 0,04) y menos complicaciones (6,0% frente a 25,4%, p = 0,002). No se encontraron diferencias significativas en la duración de la estancia hospitalaria postquirúrgica entre los grupos de cirugía laparoscópica y cirugía abierta (9,66 ± 5,42 frente a 10,64 ± 4,93, p = 0,28). El análisis de subgrupos mostró que el grupo de cirugía laparoscópica tuvo una supervivencia sin recidiva superior (χ2 = 4,14, p = 0,04) y menos complicaciones después de la cirugía (2,9% frente a 24,4%, p = 0,01) en el subgrupo de tumores del estroma gastrointestinal de recto ≤ 5 cm.LIMITACIONES:La naturaleza de la revisión retrospectiva y el período de seguimiento relativamente corto son limitaciones de este estudio.CONCLUSIONES:La cirugía laparoscópica ofrece una opción segura y factible para la resección radical de tumores primariamente localizados del estroma gastrointestinal de recto, especialmente para pacientes con tumores ≤5 cm. Consulte Video Resumen en http://links.lww.com/DCR/B764.
Assuntos
Tumores do Estroma Gastrointestinal , Laparoscopia , Neoplasias Retais , Tumores do Estroma Gastrointestinal/cirurgia , Humanos , Laparoscopia/métodos , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/cirurgia , Pontuação de Propensão , Neoplasias Retais/patologia , Neoplasias Retais/cirurgia , Estudos RetrospectivosRESUMO
BACKGROUND: To date, there is no approved blood-based biomarker for breast cancer detection. Herein, we aimed to assess semaphorin 4C (SEMA4C), a pivotal protein involved in breast cancer progression, as a serum diagnostic biomarker. METHODS: We included 6,213 consecutive inpatients from Tongji Hospital, Qilu Hospital, and Hubei Cancer Hospital. Training cohort and two validation cohorts were introduced for diagnostic exploration and validation. A pan-cancer cohort was used to independently explore the diagnostic potential of SEMA4C among solid tumors. Breast cancer patients who underwent mass excision prior to modified radical mastectomy were also analyzed. We hypothesized that increased pre-treatment serum SEMA4C levels, measured using optimized in-house enzyme-linked immunosorbent assay kits, could detect breast cancer. The endpoints were diagnostic performance, including area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. Post-surgery pathological diagnosis was the reference standard and breast cancer staging followed the TNM classification. There was no restriction on disease stage for eligibilities. RESULTS: We included 2667 inpatients with breast lesions, 2378 patients with other solid tumors, and 1168 healthy participants. Specifically, 118 patients with breast cancer were diagnosed with stage 0 (5.71%), 620 with stage I (30.00%), 966 with stage II (46.73%), 217 with stage III (10.50%), and 8 with stage IV (0.39%). Patients with breast cancer had significantly higher serum SEMA4C levels than benign breast tumor patients and normal controls (P < 0.001). Elevated serum SEMA4C levels had AUC of 0.920 (95% confidence interval [CI]: 0.900-0.941) and 0.932 (95%CI: 0.911-0.953) for breast cancer detection in the two validation cohorts. The AUCs for detecting early-stage breast cancer (n = 366) and ductal carcinoma in situ (n = 85) were 0.931 (95%CI: 0.916-0.946) and 0.879 (95%CI: 0.832-0.925), respectively. Serum SEMA4C levels significantly decreased after surgery, and the reduction was more striking after modified radical mastectomy, compared with mass excision (P < 0.001). The positive rate of enhanced serum SEMA4C levels was 84.77% for breast cancer and below 20.75% for the other 14 solid tumors. CONCLUSIONS: Serum SEMA4C demonstrated promising potential as a candidate biomarker for breast cancer diagnosis. However, validation in prospective settings and by other study groups is warranted.
Assuntos
Neoplasias da Mama , Semaforinas , Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Feminino , Humanos , Mastectomia , Estudos Prospectivos , Estudos RetrospectivosRESUMO
Stain normalization often refers to transferring the color distribution to the target image and has been widely used in biomedical image analysis. The conventional stain normalization usually achieves through a pixel-by-pixel color mapping model, which depends on one reference image, and it is hard to achieve accurately the style transformation between image datasets. In principle, this difficulty can be well-solved by deep learning-based methods, whereas, its complicated structure results in low computational efficiency and artifacts in the style transformation, which has restricted the practical application. Here, we use distillation learning to reduce the complexity of deep learning methods and a fast and robust network called StainNet to learn the color mapping between the source image and the target image. StainNet can learn the color mapping relationship from a whole dataset and adjust the color value in a pixel-to-pixel manner. The pixel-to-pixel manner restricts the network size and avoids artifacts in the style transformation. The results on the cytopathology and histopathology datasets show that StainNet can achieve comparable performance to the deep learning-based methods. Computation results demonstrate StainNet is more than 40 times faster than StainGAN and can normalize a 100,000 × 100,000 whole slide image in 40 s.