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BACKGROUND: To develop and validate a serum protein nomogram for colorectal cancer (CRC) screening. METHODS: The serum protein characteristics were extracted from an independent sample containing 30 colorectal cancer and 12 polyp tissues along with their paired samples, and different serum protein expression profiles were validated using RNA microarrays. The prediction model was developed in a training cohort that included 1345 patients clinicopathologically confirmed CRC and 518 normal participants, and data were gathered from November 2011 to January 2017. The lasso logistic regression model was employed for features selection and serum nomogram building. An internal validation cohort containing 576 CRC patients and 222 normal participants was assessed. RESULTS: Serum signatures containing 27 secreted proteins were significantly differentially expressed in polyps and CRC compared to paired normal tissue, and REG family proteins were selected as potential predictors. The C-index of the nomogram1 (based on Lasso logistic regression model) which contains REG1A, REG3A, CEA and age was 0.913 (95% CI, 0.899 to 0.928) and was well calibrated. Addition of CA199 to the nomogram failed to show incremental prognostic value, as shown in nomogram2 (based on logistic regression model). Application of the nomogram1 in the independent validation cohort had similar discrimination (C-index, 0.912 [95% CI, 0.890 to 0.934]) and good calibration. The decision curve (DCA) and clinical impact curve (ICI) analysis demonstrated that nomogram1 was clinically useful. CONCLUSIONS: This study presents a serum nomogram that included REG1A, REG3A, CEA and age, which can be convenient for screening of colorectal cancer.
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BACKGROUND: For high-risk stageIImismatch repair deficient (dMMR) colon cancers, the benefit of adjuvant chemotherapy remains debatable. The principal aim of this study was to evaluate the prognostic value of high-risk factors and the effect of oxaliplatin-based adjuvant chemotherapy among dMMR stageIIcolon cancers. METHODS: Patients with stage II dMMR colon cancers diagnosed between June 2011 and May 2018 were enrolled in the study. Clinicopathological characteristics, treatment, and follow-up data were retrospectively collected. The high-risk group was defined as having one of the following factors: pT4 disease, fewer than twelve lymph nodes harvested (< 12 LNs), poorly differentiated histology, perineural invasion (PNI), lymphatic vascular invasion (LVI), or elevated preoperative carcinoembryonic antigen (CEA). The low-risk group did not have any risk factors above. Factors associated with disease-free survival (DFS) were included in univariate and multivariate Cox analyses. RESULTS: We collected a total of 262 consecutive patients with stage II dMMR colon cancer. 179 patients (68.3%) have at least one high-risk factor. With a median follow-up of 50.1 months, the low-risk group was associated with a tended to have a better 3-year DFS than the high-risk group (96.4% vs 89.4%; P = 0.056). Both elevated preoperative CEA (HR 2.93; 95% CI 1.26-6.82; P = 0.013) and pT4 disease (HR 2.58; 95% CI 1.06-6.25; P = 0.037) were independent risk factors of recurrence. Then, the 3-year DFS was 92.6% for the surgery alone group and 88.1% for the adjuvant chemotherapy group (HR 1.64; 95% CI 0.67-4.02; P = 0.280). Furthermore, no survival benefit from oxaliplatin-based adjuvant chemotherapy was observed in the high-risk group and in the subgroups with pT4 disease or < 12 LNs. CONCLUSIONS: These data suggests that not all high-risk factors have a similar impact on stage II dMMR colon cancers. Elevated preoperative CEA and pT4 tumor stage are associated with increased recurrence risk. However, oxaliplatin-based adjuvant chemotherapy shows no survival benefits in stage II dMMR colon cancers, either with or without high-risk factors.
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Neoplasias Encefálicas , Neoplasias do Colo , Neoplasias Colorretais , Reparo de Erro de Pareamento de DNA , Síndromes Neoplásicas Hereditárias , Humanos , Estudos Retrospectivos , Oxaliplatina/uso terapêutico , Estadiamento de Neoplasias , Antígeno Carcinoembrionário , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias do Colo/cirurgia , Prognóstico , Quimioterapia AdjuvanteRESUMO
Bevacizumab plays an important role in the first and second line treatment for metastatic colorectal cancer (CRC). And induction of hypoxia and the tumors response to it plays an important role in determining the efficacy of antiangiogenic therapy while the connection between them remains unclear. Here, we found that lactate accumulated in the tumor environment of CRC and acted as substrates for histone lactylation, and this process was further induced by cellular enhanced glycolysis in hypoxia. We determined that CRC patients resistant to bevacizumab treatment presented with elevated levels of histone lactylation and inhibition of histone lactylation efficiently suppressed CRC tumorigenesis, progression and survival in hypoxia. Histone lactylation promoted the transcription of RUBCNL/Pacer, facilitating autophagosome maturation through interacting with BECN1 (beclin 1) and mediating the recruitment and function of the class III phosphatidylinositol 3-kinase complex, which had a crucial role in hypoxic cancer cells proliferation and survival. Moreover, combining inhibition of histone lactylation and macroautophagy/autophagy with bevacizumab treatment demonstrated remarkable treatment efficacy in bevacizumab-resistance patients-derived pre-clinical models. These findings delivered a new exploration and important supplement of metabolic reprogramming-epigenetic regulation, and provided a new strategy for improving clinical efficacy of bevacizumab in CRC by inhibition of histone lactylation.Abbreviations: 2-DG: 2-deoxy-D-glucose; BECN1: beclin 1; CQ: chloroquine; CRC: colorectal cancer; DMOG: dimethyloxalylglycine; H3K18la: histone H3 lysine 18 lactylation; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; Nala: sodium lactate; PDO: patient-derived orgnoid; PDX: patient-derived xenograft; RUBCNL/Pacer: rubicon like autophagy enhancer; SQSTM1/p62: sequestosome 1.
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Neoplasias Colorretais , Histonas , Humanos , Autofagia/fisiologia , Proteína Beclina-1/metabolismo , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Epigênese Genética , Histonas/metabolismo , Hipóxia , Ácido Láctico , Lisina/metabolismoRESUMO
BACKGROUND: Haloxyfop-P-methyl, an acetyl-CoA carboxylase (ACCase)-inhibiting herbicide, has been extensively used to control grass weeds. Widespread use of haloxyfop-P-methyl in cotton fields in China has led to the development of glutathione transferase (GST)-mediated resistance in Digitaria sanguinalis. An RNA-seq analysis identified DsGSTU1, a tau class glutathione transferase from the D. sanguinalis transcriptome as a potential candidate. Here, we cloned DsGSTU1 from D. sanguinalis young leaf tissues and subsequently characterized DsGSTU1 by a combination of sequence analysis, as well as functional heterologous expression in rice. RESULTS: The full-length coding DNA sequence (CDS) of DsGSTU1 is 717 bp in length. Higher DsGSTU1 expression was observed in haloxyfop-P-methyl-resistant (HR) D. sanguinalis than in haloxyfop-P-methyl-susceptible (HS) plants. Overexpression of the DsGSTU1 gene was confirmed by transformation into the wild-type (WT) Nipponbare rice with pBWA(V)HS, a recombinant expression vector. GST activity in transgenic rice seedlings was 1.18-1.40-fold higher than the WT rice seedlings before and after haloxyfop-P-methyl treatment, respectively. Additionally, transgenic rice seedlings overexpressing DsGSTU1 were less sensitive to haloxyfop-P-methyl. CONCLUSION: Our combined findings suggest that DsGSTU1 is involved in metabolic resistance to haloxyfop-P-methyl in D. sanguinalis. A better understanding of the major genes contributing to herbicide-resistant D. sanguinalis facilitates the development of resistance management strategies for this global invasive grass weed. © 2023 Society of Chemical Industry.
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Herbicidas , Oryza , Digitaria/genética , Glutationa Transferase/genética , Resistência a Herbicidas/genética , Poaceae/genética , Oryza/genética , Herbicidas/farmacologia , Clonagem Molecular , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismoRESUMO
BACKGROUND: For clinically low-risk stage III colorectal cancer, the decision on cycles of adjuvant chemotherapy after surgery is disputed. The present study investigates the use of additional biomarkers of ploidy and stroma-ratio(PS) to stratify patients with low-risk stage III colorectal cancer, providing a basis for individualized treatment in the future. METHODS: This study retrospectively enrolled 198 patients with clinical-low-risk stage III colorectal cancer (T1-3N1M0) and analyzed the DNA ploidy and stroma ratio of FFPE tumor tissues. The patients were divided into PS-low-risk group (Diploidy or Low-stroma) and PS-high-risk group (Non-diploid and High-stroma). For survival analyses, Kaplan-Meier and Cox regression models were used. RESULTS: The results showed that the 5-year DFS of the PS-high-risk group was significantly lower than that in the PS-low-risk group (78.6 vs. 91.2%, HR = 2.606 [95% CI: 1.011-6.717], P = 0.039). Besides, in the PS-low-risk group, the 5 year OS (98.2 vs. 86.7%, P = 0.022; HR = 5.762 [95% CI: 1.281-25.920]) and DFS (95.6, vs 79.9%, P = 0.019; HR = 3.7 [95% CI: 1.24-11.04]) of patients received adjuvant chemotherapy for > 3 months were significantly higher than those received adjuvant chemotherapy for < 3 months. We also found that the PS could stratify the prognosis of patients with dMMR tumors. The 5-year OS (96.3 vs 71.4%, P = 0.037) and DFS (92.6 vs 57.1%, P = 0.015) were higher in the PS-low-risk dMMR patients than those in the PS-high-risk dMMR patients. CONCLUSION: In this study, we found that PS can predict the prognosis of patients with stage III low-risk CRC. Besides, it may guide the decision on postoperative adjuvant chemotherapy.
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Neoplasias do Colo , Neoplasias Colorretais , Humanos , Neoplasias do Colo/patologia , Estudos Retrospectivos , Estadiamento de Neoplasias , Neoplasias Colorretais/terapia , Neoplasias Colorretais/tratamento farmacológico , Prognóstico , Ploidias , DNA/uso terapêutico , Quimioterapia AdjuvanteRESUMO
Inflammation is a common medical complication in colorectal cancer (CRC) patients, which plays significant roles in tumor progression and immunosuppression. However, the influence of inflammatory conditions on the tumor response to immune checkpoint inhibitors (ICI) is incompletely understood. Here we show that in a patient with high microsatellite instability (MSI-H) CRC and a local inflammatory condition, the primary tumor progresses but its liver metastasis regresses upon Pembrolizumab treatment. In silico investigation prompted by this observation confirms correlation between inflammatory conditions and poor tumor response to PD-1 blockade in MSI-H CRCs, which is further validated in a cohort of 62 patients retrospectively enrolled to our study. Inhibition of local but not systemic immune response is verified in cultures of paired T cells and organoid cells from patients. Single-cell RNA sequencing suggests involvement of neutrophil leukocytes via CD80/CD86-CTLA4 signaling in the suppressive immune microenvironment. In concordance with this finding, elevated neutrophil-to-lymphocyte ratio indicates inhibited immune status and poor tumor response to ICIs. Receiver operating characteristic curve further demonstrates that both inflammatory conditions and a high NLR could predict a poor response to ICIs in MSI- CRCs, and the predictive value could be further increased when these two predictors are combined. Our study thus suggests that inflammatory conditions in MSI-H CRCs correlate with resistance to ICIs through neutrophil leukocyte associated immunosuppression and proposes both inflammatory conditions and high neutrophil-to-lymphocyte ratio as clinical features for poor ICI response.
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Neoplasias Colorretais , Inibidores de Checkpoint Imunológico , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Inflamação/genética , Instabilidade de Microssatélites , Estudos Retrospectivos , Microambiente Tumoral/genéticaRESUMO
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.
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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
BACKGROUND: The number of colorectal cancer liver metastases (CRLMs) is usually considered a contradictory indicator to surgical resection. However, some patients with initially unresectable CRLMs can receive radical local treatment after conversion therapy. This study aimed to evaluate the effect of radical local treatment after conversion therapy and the prognosis of patients with more than 10 initially unresectable CRLMs. METHODS: Data for a total of 229 patients with initially unresectable CRLMs were retrospectively reviewed between December 2012 and January 2020. Among these patients, 107 had ≥10 CRLMs, and 122 had <10 CRLMs. Overall survival (OS) and progression-free survival (PFS) were used to reflect the prognosis of different groups of patients. Conversion therapy was defined as an initially unresectable liver metastasis converted into an R0 resectable lesion after systemic chemotherapy. Radical local treatment included hepatectomy and radiofrequency ablation (RFA). RESULTS: Patients with ≥10 CRLMs had a lower conversion rate (42.7% vs. 56.6%, p = 0.001). Baseline clinical N stage 1-2, ≥8 first-line chemotherapy courses, and stable disease (SD) according to the Response Evaluation Criteria in Solid Tumours (RECIST) were independent factors predictive of conversion failure. Primary tumour location in the right colon, RECIST response of SD, and the absence of targeted therapy were independent factors predictive of unfavourable OS. The survival curves revealed that the OS of patients with or without conversion could be distinguished only among patients with <10 CRLMs (89.9% [95% CI, 82.5%-98.0%] vs. 58.9% [95% CI, 45.2%-76.7%], p < 0.001); this cut-off point could also distinguish patients with a successful conversion outcome according to OS (89.9% [95% CI, 82.5-98.0%] vs. 58.2% [95% CI, 42.2-80.4%], p = 0.008). CONCLUSION: For CRLMs ≥ 10, patients with a successful conversion outcome cannot be distinguished from those without successful conversion outcome according to OS. Thus, conversion therapy with the intent to perform radical local treatment may not be suitable for patients with 10 or more liver metastases from colorectal cancer.
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Ablação por Cateter , Neoplasias Colorretais , Neoplasias Hepáticas , Humanos , Estudos Retrospectivos , Neoplasias Hepáticas/secundário , Hepatectomia , Neoplasias Colorretais/patologia , PrognósticoRESUMO
ß2-microglobulin (B2M) and Janus kinases 1 and 2 (JAK1/2) mutations have been suggested as genetic mechanisms of immune evasion for anti-programmed cell death protein 1 (PD-1) therapy. Whether B2M and JAK1/2 lose-of-function mutation can cause primary resistance to anti-PD-1 therapy in colorectal carcinoma (CRC) patients remains controversial. Here, we sought to compare the efficacy of anti-PD-1 therapy in DNA mismatch repair deficient/microsatellite instability-high CRC patients with or without B2M or JAK1/2 mutations. Thirty-Five CRC patients who received anti-PD-1 therapy were enrolled in this study. All tumor samples underwent next-generation sequencing. The clinical and molecular data from 110 CRC patients sequenced with the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay and accessed through cBioportal were also analyzed in this study. Of the 35 CRC patients from our center, 10 (28.6%) had a B2M loss-of-function mutation, and 8 (22.9%) had a JAK1/2 loss-of-function mutation. Compared with B2M wild-type CRCs, B2M-mutated CRCs did not show a higher frequency of resistance to anti-PD-1 therapy (P=0.71). There was even better response to anti-PD-1 therapy in patients with JAK1/2 mutation than in those without (P=0.015). Of the 110 CRC patients in the MSK-IMPACT datasets, 13 (11.8%) had a B2M mutation, and 15 (13.6%) had a JAK1/2 mutation. After analyzing the response to anti-PD-1 therapy in these 110 patients, we found similar results (P=0.438 and 0.071, respectively). Moreover, patients with B2M or JAK1/2 mutation had a lower tumor mutational burden score compared with those without. B2M and JAK1/2 loss-of-function mutations occur frequently in microsatellite instability-high CRC. Our study demonstrated that patients with CRC harboring B2M or JAK1/2 mutations should not be excluded from anti-PD-1 therapy.
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Neoplasias do Colo , Neoplasias Colorretais , Inibidores de Checkpoint Imunológico , Síndromes Neoplásicas Hereditárias , Receptor de Morte Celular Programada 1 , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Janus Quinase 1/genética , Janus Quinase 2/genética , Instabilidade de Microssatélites , Mutação , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Microglobulina beta-2/genéticaRESUMO
Resistance to chemotherapy remains the major cause of treatment failure in patients with colorectal cancer (CRC). Here, we identified TRIM25 as an epigenetic regulator of oxaliplatin (OXA) resistance in CRC. The level of TRIM25 in OXA-resistant patients who experienced recurrence during the follow-up period was significantly higher than in those who had no recurrence. Patients with high expression of TRIM25 had a significantly higher recurrence rate and worse disease-free survival than those with low TRIM25 expression. Downregulation of TRIM25 dramatically inhibited, while overexpression of TRIM25 increased, CRC cell survival after OXA treatment. In addition, TRIM25 promoted the stem cell properties of CRC cells both in vitro and in vivo. Importantly, we demonstrated that TRIM25 inhibited the binding of E3 ubiquitin ligase TRAF6 to EZH2, thus stabilizing and upregulating EZH2, and promoting OXA resistance. Our study contributes to a better understanding of OXA resistance and indicates that inhibitors against TRIM25 might be an excellent strategy for CRC management in clinical practice.
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Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Oxaliplatina/uso terapêutico , Fatores de Transcrição/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Antineoplásicos/farmacologia , Neoplasias Colorretais/genética , Humanos , Oxaliplatina/farmacologiaRESUMO
A Correction to this paper has been published: https://doi.org/10.1038/s41556-021-00686-x.
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In this work, an analogue of electromagnetically induced transparency (EIT) is excited by a periodic unit consisting of a silicon rectangular bar resonator and a silicon ring resonator in terahertz (THz). The analogue of the EIT effect can be well excited by coupling of the "bright mode" and the "dark mode" supported by the bar and the ring, respectively. Using the semimetallic properties of graphene, active control of the EIT-like effect can be realized by integrating a monolayer graphene into THz metamaterials. By adjusting the Fermi energy of graphene, the resonating electron distribution changes in the dielectric structures, resulting in the varying of the EIT-like effect. The transmission can be modulated from 0.9 to 0.3 with the Fermi energy of graphene placed under the ring resonator mold varying from 0 to 0.6 eV, while a modulation range of 0.9-0.3 corresponds to Fermi energy from 0 to 0.3 eV when graphene is placed under the rectangular bar resonator. Our results may provide potential applications in slow light devices and an ultrafast optical signal.
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Postassembly modification of peptides via C(sp3)-H functionalization provides an efficient way to prepare functionalized peptides for biological study and pharmaceutical development. In this work, we developed a new method for γ-C(sp3)-H functionalization of aliphatic side chains of N-terminus-unprotected peptides. With the N-terminal residues as directing groups, a wide range of di-, tri-, tetra-, and pentapeptides underwent C-H arylation of the residues (Val, Ile, Tle) at the +2 position from the N-terminus.
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Nitrogênio/química , Oligopeptídeos/químicaRESUMO
The histone methyltransferase SETDB1 catalyzes the addition of methyl groups to histone H3 at lysine 9, and upregulation of SETDB1 is associated with poor prognosis in cancer patients. Here, we describe how overexpression of SETDB1 contributes to colorectal cancer (CRC) tumorigenesis and drug resistance. We show that SETDB1 is upregulated in CRC, and its level correlates with poor clinical outcome. SETDB1 attenuation inhibits CRC cell proliferation Mechanistically, SETDB1 promotes cell proliferation by upregulating Akt activation. Further, SETDB1 is essential for the tumorigenic activity of Akt. Functional characterization revealed that inhibition of SETDB1 reduces cell growth in CRC resistant to targeted treatments in vitro and in vivo, KRAS-mutated CRC included. Taken together, our results indicate that SETDB1 is a major driver of CRC and may serve as a potential target for the treatment of KRAS-mutated CRC.
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Carcinogênese/efeitos dos fármacos , Cetuximab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Histona-Lisina N-Metiltransferase/genética , Idoso , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Histona Metiltransferases/genética , Histonas/genética , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BECN1 is a critical regulator of autophagy, which plays important roles in tumor formation and metastasis. However, the autophagy-independent role of BECN1 and the clinical prediction value of BECN1 still need to be explored. Here, we observed significantly lower expression of BECN1 in colorectal cancers (CRCs) compared with adjacent normal colon tissue, and downregulation of BECN1 was positively related to poor prognosis in CRC patients. In addition, we found that knockdown of BECN1 markedly promoted CRC cell motility and invasion. Bioinformatics gene set enrichment analysis (GSEA) revealed that low levels of BECN1 were significantly correlated with the STAT3 signaling pathway in CRC. Consistently, knockdown of BECN1 increased the phosphorylation of STAT3 and activated the STAT3 signaling pathway in CRC cells. Furthermore, we demonstrated that STAT3 was involved in the CRC metastasis mediated by knockdown of BECN1 in vitro and in vivo. Mechanistically, knockdown of BECN1 promoted the phosphorylation of STAT3 via regulation of the interaction between STAT and JAK2 but did not inhibit autophagy. Our study revealed that BECN1 served as a negative regulator of CRC metastasis by regulating STAT3 signaling pathway activation in an autophagy-independent manner. The BECN1/JAK2/STAT3 signaling pathway can be used as a potential therapeutic target for metastatic CRC.
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Autofagia/genética , Proteína Beclina-1/genética , Neoplasias Colorretais/genética , Metástase Neoplásica/patologia , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/genética , Neoplasias do Colo/genética , Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Camundongos Nus , Metástase Neoplásica/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais/fisiologiaRESUMO
Sine oculis homeobox homolog 4 (SIX4), a member of the SIX family, play important role in the development and construction of vertebrate tissues and organs. There is very little known about the function of SIX4 in cancer cells. Herein, we investigated whether SIX4 promote cancer metastasis in addition to its direct role in breast cancer cells. Our study showed that the expression of SIX4 was profoundly increased in breast cancer tissues, and the high expression of SIX4 correlated strongly with distant metastasis and poor prognosis. Functional experiments demonstrated that SIX4 obviously promoted the cell migration and invasion of breast cancer cells, and up-regulated the expression of EMT mesenchymal marker, down-regulated the epithelial molecules by Snai1 induction in vitro. Moreover, SIX4 knockdown significant suppressed breast cancer lung metastasis in vivo. Mechanistically, SIX4 directly interacted with STAT3 and promoted the phosphorylated STAT3 nuclear translocation, thereby inducing EMT program activation. Collectively, our findings demonstrated that SIX4 may be a promising target for intervention to prevent cancer metastasis.
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Site-selective modification of chemically and biologically valuable α-amino acids and peptides is of great importance for biochemical study and pharmaceutical development. Few methods based on remote C(sp3)-H functionalization of aliphatic side-chains of peptides has been disclosed in recent years. In this report, we developed a novel approach for γ-C(sp3)-H and γ-/δ-C(sp2)-H arylation of α-amino acids with α-hydrogen by native amine-directed C-H functionalization and further realized the γ-C(sp3)-H arylation of N-terminally unprotected peptides.
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Aminoácidos/química , Oligopeptídeos/química , Aminas/química , Carbono/química , Prata/químicaRESUMO
Angiogenesis plays important roles in solid tumors progression. Growth factors such as vascular endothelial growth factors (VEGFs) can induce angiogenesis and hypoxia promotes the expression of VEGFs through activating hypoxia-inducible factor 1 (HIF-1α). However, the regulation of HIF-1α still not been fully understood. Here, we demonstrate that the Sine Oculis Homeobox Homolog 4 (SIX4) is up-regulated in colorectal cancer (CRC) and high expression of SIX4 predicts a poor prognosis. Overexpression of SIX4 enhances tumor growth and angiogenesis in vitro and in vivo, while knockdown of SIX4 inhibits tumor growth and angiogenesis. Furthermore, we show that SIX4 increases the expression of VEGF-A by coordinating with the HIF-1α. Mechanically, we explore that SIX4 up-regulates the expression of HIF-1α depending on Akt activation. Collectively, we demonstrate that SIX4 is functional in regulating tumor angiogenesis and SIX4 might be used as anti-angiogenic therapy in CRC.
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Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/irrigação sanguínea , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Neovascularização Patológica/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transativadores/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Proteínas de Homeodomínio/genética , Humanos , Metástase Linfática , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Neovascularização Patológica/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Transdução de Sinais , Taxa de Sobrevida , Transativadores/genética , Células Tumorais Cultivadas , Cicatrização , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Free amino group-directed C(sp3)-H functionalization of aliphatic amines is a fundamental challenge in synthetic organic chemistry. Also, the NH2-directed C(sp3)-H functionalization of α-amino acids and their derivatives remains barely explored. With palladium as the catalyst and Ag2O as the additive, we developed the first NH2-directed γ-C(sp3)-H arylation of α-amino esters with diaryliodonium triflates for the construction of synthetically useful γ-aryl-α-amino esters, and the result of the KIE study suggested that the catalytic reaction involved an irreversible C-H cleavage as the rate-determining step.
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The serine/threonine kinase Akt plays a central role in cell proliferation, survival and metabolism, and its hyperactivation is linked to cancer progression. Here we report that Akt undergoes K64 methylation by SETDB1, which is crucial for cell membrane recruitment, phosphorylation and activation of Akt following growth factor stimulation. Furthermore, we reveal an adaptor function of histone demethylase JMJD2A, which is important for recognizing Akt K64 methylation and recruits E3 ligase TRAF6 and Skp2-SCF to the Akt complex, independently of its demethylase activity, thereby initiating K63-linked ubiquitination, cell membrane recruitment and activation of Akt. Notably, the cancer-associated Akt mutant E17K displays enhanced K64 methylation, leading to its hyper-phosphorylation and activation. SETDB1-mediated Akt K64 methylation is upregulated and correlated with Akt hyperactivation in non-small-cell lung carcinoma (NSCLC), promotes tumour development and predicts poor outcome. Collectively, these findings reveal complicated layers of Akt activation regulation coordinated by SETDB1-mediated Akt K64 methylation to drive tumorigenesis.