ANALYTICAL SCIENCES
·
2018
·Vol. 35
·期 4
·441-448
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IF 1.355
Wang Xiaojing,Yang Mei,Liu Qingyan,Yang Siyi,Geng Xintong,Yang Yixia,Fa Huanbao,Wang Yongzhong,Hou Changjun
In this paper, an ultrasensitive electrochemical biosensor based on carboxylated multi-walled carbon nanotube/molybdenum disulfide composites (MWCNTs-COOH/MoS 2 ) for the detection of KRAS gene is described. An easy, low-cost method, named one-step hydrothermal, was used for the synthesize of MWCNTs-COOH/MoS 2 nanocomposites, and scanning electronic microscopy (SEM), high resolution transmission electron microscopy (HRTEM), Fourier transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS) and X-ray diffraction (XRD) were used for characterizing the prepared composites. Furthermore, cyclic voltammetry (CV) and differential pulse voltammetry (DPV) were employed for an electrochemical performance study of this biosensor. Under optimal conditions, the detection limit of target DNA achieved down to 3 fM ( S / N = 3) with high sensitivity; the linear range with the logarithm of the concentrations of target DNA varied from 1.0 × 10 −14 to 1.0 × 10 −7 M. Finally, the practicality of our proposed sensor was verified by a determination of the KRAS gene in human serum samples with good accuracy and high precision due to the excellent conductivity and large active surface area of the MWCNTs-COOH/MoS 2 nanocomposites. This proposed biosensor thus provides a practical method for the rapid and sensitive analysis of gene detection.
研究领域:
纳米技术
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生物传感器
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电化学
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基因检测
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材料科学
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DOI
PubMed
高影响因子
Bioactive Materials
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2023
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IF 18.9
Yong Mei,Xiaohua Qin,Zhenyu Yang,Shiyao Song,Xiaoting Liu,Chong Wu,Jieying Qian,Xiaowan Huang,Yunjiao Zhang,Weiling He
KRAS-TP53 co-mutation is strongly associated with poor prognosis and high malignancy in gastrointestinal cancers. Therefore, a novel approach to oncotherapy may lie in combination therapy targeting both KRAS and TP53 . Herein, we present a novel self-assembled nanoparticle (HA-TPP/A) that are functionalized nano-carrier hyaluronic acid (HA)-TPP conjugate (HA-TPP) to degrade mutant p53 proteins (mutp53) and co-deliver AMG510 for treating KRAS-TP53 co-alteration of gastrointestinal cancers by inhibiting the mutant KRAS and mutp53 signaling pathways. The HA-TPP/A nanoparticles led to ubiquitination-dependent proteasomal degradation of mutp53 by targeting damage to mitochondria. Furthermore, these nanoparticles abrogated the gain-of-function (GOF) phenotypes of mutp53 and increased sensitivity to AMG510-induced cell killing, thereby reducing cell proliferation and migration in gastrointestinal cancer with KRAS-TP53 co-mutation. The co-loaded HA-TPP/A nanoparticles demonstrated remarkable therapeutic efficacy in a tumor-bearing mouse model, particularly in KRAS-TP53 double mutant expressing cancer cells, compared with single drug and combined free drug groups. Notably, HA-TPP/A is the first reported nanoparticle with an ability to co-target KRAS-TP53 , providing a promising approach for therapy in highly malignant gastrointestinal tumors and potentially expanding clinical indications for AMG510 targeted therapies in gastrointestinal tumors.
研究领域:
肿瘤学
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药学
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纳米技术
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分子生物学
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产品关联
DOI
PubMed
高影响因子
APOPTOSIS
·
2026
·Vol. 31
·期 9
·210
·
IF 9
Xie Jingyi,Wang Simeng,Liu Juan,Zhang Yan,Zhu Haixiao,Cui Rongrong,Yao Yao,Yu Wei,Hou Peng
KRAS mutations are among the most common genetic alterations in colorectal cancer (CRC) and are strongly linked to poor prognosis and therapeutic resistance. However, current treatments targeting KRAS-mutated CRC have shown limited clinical efficacy. Argonaute 2 (AGO2) is a critical component in microRNA (miRNA)-mediated gene silencing complex, which is involved in the maturation of miRNAs and the regulation of target genes. It has been reported that mutated KRAS can interact with AGO2 and impair its function, thereby amplifying the oncogenic potency of mutant KRAS and accelerating tumor progression. To explore the therapeutic implications of this interaction, we developed a peptide inhibitor and engineered peptide-gold nanoparticles (Au-pep) that specifically disrupted KRAS-AGO2 interaction, which dramatically attenuated the malignant phenotype of KRAS-mutated CRC cells. Mechanistically, Au-pep-mediated disruption of the KRAS-AGO2 complex led to partial restoration of the miRNA expression landscape, with let‑7c‑5p emerging as the most significantly up‑regulated effector. As a result, restored let-7c-5p caused a significant down-regulation of key oncogenic drivers (KRAS, c-Myc and Bcl2) to suppress the growth of KRAS-mutated CRC cells and induce their apoptosis. Furthermore, this miRNA restoration conferred dual therapeutic benefits by sensitizing KRAS-mutated CRC cells to 5-fluorouracil (5-FU) via ABCC5 repression and augmenting immunotherapy responsiveness via PD-L1 down-regulation. Our findings, taken together, delineate a new therapeutic paradigm with significant translational potential for improving clinical outcomes in this recalcitrant patient population.
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DOI
高影响因子
MOLECULAR THERAPY
·
2025
·
IF 12
Xinyuan Liu,Jiaqi Yang,Sicong Huang,Yifan Hong,Yupeng Zhu,Jianing Wang,Yi Wang,Tingbo Liang,Xueli Bai
KRAS mutations are instrumental in the development and progression of pancreatic ductal adenocarcinoma (PDAC). Nevertheless, the efficacy of direct targeting of KRAS mutations to inhibit tumor development remains doubtful. It is therefore necessary to gain a deeper insight into the mechanism in which KRAS mutations influence the effectiveness of clinical treatments. In this study, KRAS G12D protein was detected in cancer-associated fibroblasts (CAFs) from clinical samples of pancreatic ductal adenocarcinoma (PDAC). In vitro experiments demonstrated that KRAS G12D protein in CAFs was not expressed from its own mutant gene but was derived from the ingestion of tumor cell-derived extracellular vesicles (EVs). The presence of KRAS G12D protein in CAFs resulted in enhanced proliferation and migration. Furthermore, KRAS G12D -containing CAFs were observed to promote tumor chemoresistance to gemcitabine treatment both in vitro and in vivo . Application of a KRAS mutation-specific inhibitor, MRTX1133, has been demonstrated to reverse chemoresistance in PDAC. Moreover, clinical data suggest that patients with KRAS mutations have poorer prognosis following adjuvant chemotherapy. These findings elucidate the mechanism by which oncogenic KRAS mutations promote cancer chemoresistance and remodel tumor environment in a non-autonomous manner, suggesting a novel strategy for targeting KRAS mutations to enhance chemosensitivity in PDAC.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2025
·
IF 13.2
Jing Ye,Chunyan Liu,Yunshan Zhang,Xianzhong Feng,Diming Zhang
The analysis of single nucleotide polymorphism (SNP) is an effective approach for evaluating tumor initiation and progression. However, the high homology between wild-type and mutant sequences poses challenges in distinguishing between them. Additionally, many cancer-related genes harbor numerous distinct mutations, leading to a lack of efficient and practical methods for analyzing SNPs markers. In this study, we report an electrochemical method for the specific detection of SNPs using competitive bridge probes (CBPs). Through rational design, the CBPs can detect multiple mutant alleles from the same region of the gene. All SNPs-induced probe recognition and bridge-hybridization introduce nanozyme sensitizing factors into the electrochemical sensing system, which catalyze the decomposition of hydrogen peroxide, generating a significant electrochemical signal. As a proof of concept, the proposed biosensor has demonstrated to quantitatively detect various target KRAS variants. Given the high sensitivity, accessibility and versatility of the detection results, we believe the electrochemical biosensing platform we designed holds potential for future applications in cancer clinical diagnosis.
研究领域:
分子生物学
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肿瘤学
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生物传感技术
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产品关联
DOI
高影响因子
RESPIRATORY RESEARCH
·
2026
·
IF 5.7
Yi Yanjun,Hu Yidu,Ren Shencheng,Wu Yingting,Chen Xinran,Lu Yang,Yu Qi,Zuo Di,Bi Guoshu,Wang Qun,Zhan Cheng,Bian Yunyi
Background KRAS G12C-targeted therapies have transformed the treatment of KRAS G12C-mutant lung adenocarcinoma. However, acquired resistance to these therapies, whose underlying molecular mechanisms are not fully understood, presents a major obstacle to achieving long-term therapeutic success. The purpose of this study was to elucidate the mechanisms of acquired resistance to KRAS G12C inhibitors and identify potential regulators of resistance in lung adenocarcinoma. Methods Two lung adenocarcinoma cell lines (H23 and H2122) were exposed to escalating doses of two novel KRAS G12C inhibitors, fulzerasib and garsorasib, to generate resistant variants. Transcriptomic profiling was conducted to identify genes consistently upregulated in resistant cells. CRISPR/Cas9-mediated knockout (MXD4-KO) and siRNA-mediated knockdown of MXD4 were performed to assess its role in drug resistance. Mechanistic investigations employed inhibitors of ferroptosis, apoptosis, and necrosis, along with assays measuring lipid peroxidation and malondialdehyde levels. Further analysis included ferroptosis-related gene expression profiling, lipidomic profiling, ChIP-Seq, ChIP-qPCR, and dual-luciferase reporter assays. The findings were validated in patient-derived organoids (PDOs) and nude mouse models. Results Transcriptomic profiling identified 11 genes consistently upregulated in resistant cells, with MXD4 emerging as a key resistance regulator. CRISPR/Cas9-mediated knockout of MXD4 restored sensitivity to fulzerasib, garsorasib, sotorasib, and adagrasib, an effect fully reversed upon MXD4 re-overexpression. Similarly, siRNA-mediated knockdown of MXD4 in resistant cells restored drug sensitivity. Mechanistic studies revealed that MXD4 specifically suppresses ferroptosis, rather than apoptotic or necrotic pathways, by repressing ACSL4 expression and blocking its catalytic synthesis of phosphatidylethanolamine-polyunsaturated fatty acids (PE-PUFAs). ACSL4 knockout or overexpression abolished MXD4’s ability to promote ferroptosis suppression and resistance to KRAS G12C inhibitors. ChIP-Seq, ChIP-qPCR, and dual-luciferase reporter assays confirmed that MXD4 directly binds to and represses the ACSL4 promoter. These findings were validated in PDOs and nude mouse models, where MXD4 knockout restored therapeutic sensitivity, while ACSL4 knockout blocked MXD4’s resistance-promoting effects. Conclusions This study uncovers a novel resistance mechanism in which MXD4 transcriptionally silences ACSL4 to suppress ferroptosis, enabling cancer cells to evade KRAS G12C inhibitors. Targeting the MXD4-ACSL4 axis represents a promising strategy to overcome therapeutic resistance in KRAS G12C-mutant lung cancer, potentially improving long-term treatment outcomes.
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DOI
高影响因子
LANGMUIR
·
2022
·
IF 4.331
Yao Wang,Yuanli Wang,Fangrong Hu,Lizhen Zeng,Zhencheng Chen,Mingzhu Jiang,Shangjun Lin,Wei Guo,Dongxia Li
Owing to their stability in bodily fluids, exosomes have attracted increased attention as colorectal cancer (CRC) biomarkers for early diagnosis. To validate the potential of the plasma exosomes as a novel biomarker for the monitoring of CRC, we demonstrated a terahertz (THz) metamaterials (MMs) biosensor for the detection of exosomes in this work. The biosensor with two resonant frequencies is designed using full wave electromagnetic simulation software based on the finite integration time domain (FITD) method and fabricated by a surface micromachining process. The biosensor surface is first modified using Au nanoparticles (AuNPs), and then, anti-KRAS and anti-CD147, which are specific to the exosomes, are modified on the AuNPs assembled with HS-poly(ethylene glycol)-COOH (HS-PEG-COOH). Exosomes used in the experiment are extracted via the instructions in the exosomes isolation and purification kit and identified by using transmission electron microscopy (TEM), Western blot (WB), and nanoparticle tracking analysis (NTA). The biosensor covered with plasma-derived exosomes of CRC patients has a different resonance frequency shift compared to that with healthy-control-derived exosomes. This study proposes an emerging and quick method for diagnosing the CRC.
研究领域:
生物医学工程
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癌症诊断
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纳米技术
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产品关联
DOI
PubMed
高影响因子
MICROCHIMICA ACTA
·
2021
·Vol. 189
·期 1
·1-10
·
IF 5.833
Meng Yuchan,Qin Nana,Hun Xu
ZnSe nanodisks:Ti 3 C 2 MXene complex was prepared for the first time. Based on its remarkable photoelectrochemical performance, combined with the enzyme-free toehold-mediated strand displacement reaction, a photoelectrochemical biosensor for the detection of the non-small-cell cancer biomarker ctDNA KRAS G12D was developed. ZnSe nanodisks were in situ grown on Ti 3 C 2 MXene surface by two-step hydrothermal method. The high conductivity and adjustable band gap of MXene significantly enhanced the photoelectric response of ZnSe. Subsequently, the photoelectrochemical biosensor was prepared by combining with the signal amplification function of p- aminophenol and the enzyme-free toehold-mediated strand displacement reaction on the modified ITO electrode surface. Under the optimized conditions, the linear detection range is 0.5 ~ 100.0 fM, and the detection limit is 0.2 fM, which realizes the sensitive detection of KRAS G12D. The photoelectrochemical biosensor constructed opens up a new pathway for the preparation of new Mxene-based composite materials and the research of photoelectrochemical biosensor. Graphical abstract Nucleic acid liquid biopsy with ZnSe nanodisks:Ti 3 C 2 MXene photoelectroactive modified electrode
研究领域:
材料科学
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生物医学工程
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分析化学
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癌症诊断
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产品关联
DOI
PubMed
高影响因子
CANCER RESEARCH
·
2025
·Vol. 85
·期 20
·3999-4017
·
IF 16.6
Zhao Jian,Zhang Weijie,Zeng Yuanyuan,Lu Di,Ma Chenkang,Zhang Mengzhu,Cai Xin,Huang Zhifan,Yang Hongli,Li Jianjun,Zhu Jianjie,Huang Jian-An,Liu Zeyi
Despite progress in tumor-targeted therapy, oncogenic KRAS remains a major challenge in treating lung adenocarcinoma. In clinical practice, KRAS G12C inhibitors have limited response rates and are associated with acquired drug resistance. Cuproptosis is a recently identified form of copper (Cu)-mediated cell death, and previous studies have revealed that Cu metabolism plays an important role in the development of KRAS-driven tumors. In this study, we revealed the therapeutic value of the Cu ionophore elesclomol (ES) for treating KRAS G12 -mutant–driven lung adenocarcinoma. KRAS G12 -mutant lung adenocarcinoma cells relied on the Cu exporter ATP7A to maintain Cu homeostasis. ES induced cellular Cu accumulation and cuproptosis by upregulating the expression of the E3 ligase OSTM1, which interacted with the IRGY motif of ATP7A to promote ubiquitination and degradation. KRAS G12D transgenic mice and lung cancer organoids derived from the mice were used to validate the therapeutic effects of ES and Cu in vivo and in vitro . These findings indicate that KRAS G12 -driven lung adenocarcinoma relies on ATP7A-mediated Cu metabolic homeostasis, which can be perturbed with ES as an effective treatment strategy. Significance: The copper ionophore elesclomol is effective for treating KRAS-driven lung cancer by activating the OSTM1-ATP7A regulatory axis to perturb copper metabolism homeostasis.
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DOI
PubMed
高影响因子
Journal of Zhejiang University-SCIENCE B
·
2024
·Vol. 25
·期 1
·51-64
·
IF 4.7
Xu Mingming,Liu Zhaoliang,Hu Wenhua,Han Ying,Wu Zhen,Chen Sufeng,Xia Peng,Du Jing,Zhang Xumin,Hao Piliang,Xia Jun,Yang Shuang
Pancreatic cancer is among the most malignant cancers, and thus early intervention is the key to better survival outcomes. However, no methods have been derived that can reliably identify early precursors of development into malignancy. Therefore, it is urgent to discover early molecular changes during pancreatic tumorigenesis. As aberrant glycosylation is closely associated with cancer progression, numerous efforts have been made to mine glycosylation changes as biomarkers for diagnosis; however, detailed glycoproteomic information, especially site-specific N -glycosylation changes in pancreatic cancer with and without drug treatment, needs to be further explored. Herein, we used comprehensive solid-phase chemoenzymatic glycoproteomics to analyze glycans, glycosites, and intact glycopeptides in pancreatic cancer cells and patient sera. The profiling of N -glycans in cancer cells revealed an increase in the secreted glycoproteins from the primary tumor of MIA PaCa-2 cells, whereas human sera, which contain many secreted glycoproteins, had significant changes of glycans at their specific glycosites. These results indicated the potential role for tumor-specific glycosylation as disease biomarkers. We also found that AMG-510, a small molecule inhibitor against Kirsten rat sarcoma viral oncogene homolog ( KRAS ) G12C mutation, profoundly reduced the glycosylation level in MIA PaCa-2 cells, suggesting that KRAS plays a role in the cellular glycosylation process, and thus glycosylation inhibition contributes to the anti-tumor effect of AMG-510.
研究领域:
肿瘤学
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蛋白质组学
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分子生物学
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癌症生物学
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产品关联
DOI
PubMed
高影响因子
MICROCHIMICA ACTA
·
2024
·Vol. 191
·期 6
·1-10
·
IF 5.3
Wang Lanyue,Bu Sisi,Xu Shijie,Huang Tuo,Yang Fang,Tan Qianglong,Deng Minxin,Xie Wenlin,Cai Bobo,Chen Jian
Single nucleotide polymorphism (SNP) biosensors are emerging rapidly for their promising applications in human disease prevention diagnosis, treatment, and prognosis. However, it remains a bottleneck in equipping simple and stable biosensors with the traits of high sensitivity, non-enzyme, and low cost. Double base mismatches mediated chain displacement reactions have attracted fascinating advantages of tailorable thermodynamics stability, non-enzyme, and excellent assembly compliance to involvement in SNP identification. As the base mismatch position and amount in DNA sequence can be artificially adjusted, it provides plenty of selectivity and specificity for exploring perfect biosensors. Herein, a biosensor with double base mismatches mediated catalytic hairpin assembly (CHA) is designed via one base mismatch in the toehold domain and the other base mismatch in the stem sequence of hairpin 1 (H1) by triggering CHA reaction to achieve selective amplification of the mutation target (MT) and fluorescence resonance energy transfer (FRET) effect that is composed of Cy3 and Cy5 terminally attached H1 and hairpin 2 (H2). Depending on the rationally designed base mismatch position and toehold length, the fabricated biosensors show superior SNP detection performance, exhibiting a good linearity with high sensitivity of 6.6 fM detection limit and a broad detection abundance of 1%. The proposed biosensor can be used to detect the KRAS mutation gene in real samples and obtain good recoveries between 106 and 116.99%. Remarkably, these extendible designs of base mismatches can be used for more types of SNP detection, providing flexible adjustment based on base mismatch position and toehold length variations, especially for their thermodynamic model for DNA-strand displacement reactions. Graphical Abstract
研究领域:
分子生物学
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生物传感技术
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医学诊断
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产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
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2024
·
IF 6.9
Xia Rui-xue,Zou Pei-chen,Xie Jun-ting,Tang Ya-bin,Gong Miao-miao,Fan Fu,Aihemaiti Ayinazhaer,Liu Yu-qing,Shen Ying,Zhou Bin-bing S.,Zhu Liang,Lei Hui-min
RAS is the most frequently mutated oncoprotein for cancer driving. Understanding of RAS biology and discovery of druggable lynchpins in RAS pathway is a prerequisite for targeted therapy of RAS-mutant cancers. The recent identification of KRAS G12C inhibitor breaks the “undruggable” curse on RAS and has changed the therapy paradigm of KRAS-mutant cancers. However, KRAS mutations, let alone KRAS G12C mutation, account for only part of RAS-mutated cancers. Targeted therapies for cancers harboring other RAS mutations remain the urgent need. In this study we explored the pivotal regulatory molecules that allow for broad inhibition of RAS mutants. By comparing the expression levels of nucleotide pyrophosphatase (NPPS) in a panel of cell lines and the functional consequence of increased NPPS expression in RAS-mutant cells, we demonstrated that cancer cells with various kinds of RAS mutations depended on NPPS for growth and survival, and that this dependence conferred a vulnerability of RAS-mutant cancer to treatment of NPPS inhibition. RAS-mutant cells, compared with RAS-wildtype cells, bored and required an upregulation of NPPS. Transcriptomics and metabolomics analyses revealed a NPPS-dependent hyperglycolysis in RAS-mutant cells. We demonstrated that NPPS promoted glucose-derived glycolytic intermediates in RAS-mutant cells by enhancing its interaction with hexokinase 1 (HK1), the enzyme catalyzing the first committed step of glycolysis. Pharmacological inhibition of NPPS-HK1 axis using NPPS inhibitor Enpp-1-IN-1 or HK1 inhibitor 2-deoxyglucose (2-DG), or genetic interfere with NPPS suppressed RAS-mutant cancers in vitro and in vivo. In conclusion, this study reveals an unrecognized mechanism and druggable lynchpin for modulation of pan-mutant-RAS pathway, proposing a new potential therapeutic approach for treating RAS-mutant cancers.
研究领域:
肿瘤学
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分子生物学
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癌症治疗
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DOI
高影响因子
危险品化学品经营许可证（带存储）