International Journal of Biological Sciences
·
2022
·
IF 10.75
Wuping Yang,Kenan Zhang,Zedan Zhang,Jingcheng Zhou,Lei Li,Yawei Xu,Jianhui Qiu,Lin Cai,Yanqing Gong,Kan Gong
Our previous study has proved that down-regulation of CLDN10 (Claudin-10) in ccRCC (clear cell renal cell carcinoma) was closely related to tumor metastasis and predicted an unfavorable prognosis by analyzing TCGA-KIRC data. However, the effects of CLDN10 on the progression of ccRCC and its mechanisms of action remain elusive. During the study, a large number of clinical samples were utilized to verify the reduced expression of CLDN10 in ccRCC and its association with tumor metastasis and poor prognosis, and our results confirmed that lower CLDN10 expression was an independent predictor of shorter OS (HR: 4.0860, 95%CI: 2.4737-6.7490, P<0.0001) and DFS (HR: 4.3680, 95%CI: 2.2800-8.3700, P<0.0001) in metastatic ccRCC patients. CLDN10 overexpression accelerated cell apoptosis and restrained cell proliferation, migration and invasion in vitro . Besides, CLDN10 overexpression suppressed ccRCC growth and lung metastasis and promoted apoptosis in orthotopic models. Mechanistically, we found that CLDN10 overexpression up-regulated the acetylation and expression levels of ATP5O (ATP synthase subunit O, mitochondrial), leading to the dysfunction of mitochondrial, thereby suppressing the growth and metastasis of ccRCC through increasing the levels of NDUFS2, ROS, Cleaved-Caspase 3, E-cadherin and SDHB and decreasing the levels of N-cadherin and mitochondrial membrane potential. Moreover, knockdown of ATP5O expression based on the overexpression of CLDN10 could reverse the increase in NDUFS2, ROS, Cleaved-Caspase 3, E-cadherin and SDHB levels, the decrease in N-cadherin and mitochondrial membrane potential levels and the inhibition of ccRCC phenotypes caused by CLDN10 overexpression. Taken together, these findings for the first time illuminate the mechanism by which CLDN10 overexpression suppresses the growth and metastasis of ccRCC.
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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癌症研究
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DOI
PubMed
高影响因子
CytoJournal
·
2024
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IF 2.5
Jing Du,Shuhan Wu,Jiayan Liu,Bo Guo,Jianhui Li,Wenhan Li,Ying Zhang,Hengtao Song,Wenjun Shu,Zhenzhen Li,Xulong Zhu
Objective:
Metaplastic breast carcinoma (MBC) is a special type of morphologically heterogeneous and aggressively invasive breast cancer. MBC is characterized by the transformation of tumor epithelium into squamous epithelium and/or mesenchymal components, including differentiation into spindle cells, chondrocytes, and osteocytes. Due to its rarity and invasiveness, there is a paucity of research on MBC prognosis. Furthermore, there are currently no treatment guidelines for MBC. This study analyzed the clinicopathological characteristics, immunophenotype, and prognostic features of MBC. Our aim was to better characterize MBC, thereby identifying potential prognostic factors and new treatment methods. Moreover, we also describe an MBC case treated experimentally with anti-vascular targeted therapy.
Material and Methods:
We retrospectively analyzed clinical pathological data on 54 female patients with MBC from Shaanxi Provincial People’s Hospital and the XiJing Hospital of Air Force Medical University. These cases were diagnosed with MBC between January 1st, 2013, and October 1st, 2018. All patients were from the northwest region of China. The gross morphological, histological, and immunohistochemical features of MBC were analyzed. Kaplan–Meier analysis was used to calculate the survival rate, and univariate analysis was performed to identify significant prognostic factors. In addition, the treatment of an MBC patient with anti-angiogenic therapy was described, and a relevant literature review was conducted.
Results:
MBC was diagnosed in 32 left breasts and 22 right breasts from 54 women aged 21–76 years (median age of 57 years). The maximum tumor diameter ranged from 0.6 to 14 cm (average of 4.1 cm). Of the 54 patients, 47 underwent surgical treatment, with lymph node metastasis found in 17.0% (8/47). According to the World Health Organization classification criteria for breast tumors, the study cohort consisted of 15 cases of squamous cell carcinoma, ten cases of spindle cell carcinoma, nine cases of carcinoma with associated stromal differentiation, 18 cases of mixed carcinoma, and two cases of adenocarcinoma with squamous differentiation. Based on the American Joint Committee on Cancer clinical staging criteria, the patients were classified as Stage I (10 cases, 18.5%), Stage II (26 cases, 48.1%), Stage III (11 cases, 20.4%), and Stage IV (7 cases, 13.0%). Immunohistochemical analysis revealed that 94.4% of patients had triple-negative breast cancer (TNBC), 47 cases showed mutant tumor protein 53 (TP53) expression, 29 cases showed positive epidermal growth factor receptor (EGFR) expression, 43 cases showed positive E-cadherin expression, and 37 cases showed positive Cluster of Differentiation 24 expression. The Ki-67 index ranged from 20% to 90%. Univariate analysis showed that the Ki-67 index was not significantly associated with either progression-free survival (PFS) or overall survival (OS) in MBC patients. Patients with negative axillary lymph nodes had significantly better PFS and OS than those with positive nodes (P < 0.05), and patients with clinical stage I-II disease had better PFS and OS than those with stage III-IV disease (P < 0.05). Patients treated with anthracycline-containing chemotherapy had significantly better PFS than those who did not receive chemotherapy. Univariate analysis revealed that the high expression of EGFR correlated with worse PFS (P < 0.05). The type of surgical approach employed did not affect the prognosis of MBC patients. Following the application of anti-angiogenic therapy, a rapid partial response was observed in an MBC patient with carcinoma and associated stromal differentiation. This patient subsequently underwent surgery and radiation therapy and has now achieved over 6 years of PFS.
Conclusion:
MBC is a heterogeneous group of tumors with high malignancy and poor prognosis. The large majority is TNBC and exhibits unique immune phenotypes. The poor PFS of MBC patients may be related to EGFR expression, which could become a potential therapeutic target in these patients. Surgery remains the primary treatment method for MBC. The present study found that sentinel lymph node biopsy was feasible in appropriate patients, and that chemotherapy regimens incorporating anthracycline-class drugs did not appear to improve OS. Anti-angiogenic therapy holds promise as a potentially effective treatment approach for MBC, and the optimization of systemic treatment strategies should be a priority in the management of these patients.
Keywords: Metaplastic breast carcinoma, prognostic factors, anti-angiogenic targeted therapy, epidermal growth factor receptor, progression-free survival
研究领域:
肿瘤学
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病理学
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分子生物学
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DOI
PubMed
高影响因子
International Journal of Biological Sciences
·
2021
·
IF 6.582
Deng-Pan Wu,Yan Zhou,Li-Xiang Hou,Xiao-Xiao Zhu,Wen Yi,Si-Man Yang,Tian-Yu Lin,Jin-Lan Huang,Bei Zhang,Xiao-Xing Yin
Tamoxifen (TAM) resistance has indicated a significant challenge during endocrine therapy for hormone-sensitive breast cancer. Thus, it is significant to elucidate the molecular events endowing TAM resistance to endocrine therapy. In this study, we found that epithelial-mesenchymal transition (EMT) was an important event to confer TAM resistance, and attenuating EMT by elevating connexin (Cx) 43 expression could reverse TAM resistance. Specifically, Cx43 overexpression improved TAM sensitivity, while Cx43 depletion facilitated TAM insensitivity by modulating EMT in T47D TAM-resistant and -sensitive cells, and transplanted xenografts. Importantly, we found a novel reciprocal regulation between Cx43 and c-Src/PI3K/Akt pathway contributing to EMT and TAM resistance in breast cancer. Moreover, we identified that Cx43 deficiency was significantly correlated with poor relapse-free survival in patients undergoing TAM treatment. Therefore, Cx43 represents a prognostic marker and an attractive target for breast cancer treatments. Therapeutic strategies designed to increase or maintain Cx43 function may be beneficial to overcome TAM resistance.
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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产品关联
DOI
PubMed
高影响因子
BULLETIN DU CANCER
·
2023
·
IF 1.2
Siyan Zhang,Xingyao Zhang,Dong Zhang,Liang Wei,Bin Xiong,Qi Meng,Shougang Jiang
Summary Introduction Gambogic acid (GA) as an active compound isolated from Gamboge, have been investigated for many years and proved to be a promising natural anticancer agent for clinical treatment . This study aimed to investigate the inhibitory effect of docetaxel (DTX) combined with gambogic acid on bone metastasis of lung cancer. Methods The anti-proliferation effect of the combination of DTX and GA on Lewis lung cancer (LLC) cells was determined by MTT assays . The anticancer effect of the combination of DTX and GA on bone metastasis of lung cancer in vivo was explored. Evaluation of the efficacy of drug therapy was performed by comparing the degree of bone destruction and the pathological section of bone tissue of the treated mice with that of the control mice. Results In vitro cytotoxicity, cell migration, and osteoclast-induced formation assay showed that GA enhanced the therapeutic effect of DTX in Lewis lung cancer cell with a synergistic effect. In an orthotopic mouse model of bone metastasis, the average survival of the DTX + GA combination group (32.61d ± 1.06 d) was significantly increased compared with that of the DTX group (25.75 d ± 0.67 d) or GA group (23.99 d ± 0.58 d), * P < 0.01. Conclusion The combination of DTX and GA has synergistic effect and resulted in more effective inhibition of tumor metastasis , providing a strong preclinical rationale for the clinical development of the DTX + GA combination for treating bone metastasis of lung cancer.
研究领域:
肿瘤学
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
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2021
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IF 12.479
Yurui Xu,Xiaomin Zhang,Getian Hu,Xiaotong Wu,Yuanyuan Nie,Heming Wu,Desheng Kong,Xinghai Ning
Cell-based drug delivery system holds a great promise in anticancer treatment, due to its potential of maximizing therapeutic efficacy while minimizing adverse effects. However, current cell system can only deliver drugs in tumor lesions, but lack an ability to target subcellular locus of therapeutic actions, thereby compromising anticancer efficacy. Herein, we bioengineered living neutrophils as a novel type of “Photoactive neutrophil” (PAN) with capabilities of self-amplified multistage targeting and inflammation response for enhancing mitochondria-specific photo-chemotherapy. PAN encapsulated multifunctional nanocomplex (RA/Ce6) of RGD-apoptotic peptide conjugate (RA) decorated liposomal photosensitizer Ce6, and could overcome tumor barriers to selectively release RA/Ce6 within tumor. Consequently, RA/Ce6 actively entered cancer cells and accumulated in mitochondria to trigger combined photodynamic therapy (PDT) and RA-induced mitochondrial membrane disruption, resulting in enhanced therapeutic effects. Importantly, PAN exhibited inflammation amplified tumor targeting after PDT, and initiated combined photo-chemotherapy to suppress tumor growth without adverse effects, leading to prolonged mice survival. Therefore, PAN represents the first multistage targeted cell therapy , and brings new insights into cancer treatment.
研究领域:
癌症治疗
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生物医学工程
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药学
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细胞生物学
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光医学
✓ 已验证
DOI
PubMed
高影响因子
ACS Central Science
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2023
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IF 18.2
Zhicheng Le,Qi Pan,Zepeng He,Hong Liu,Yi Shi,Lixin Liu,Zhijia Liu,Yuan Ping,Yongming Chen
Intracellular delivery of therapeutic biomacromolecules is often challenged by the poor transmembrane and limited endosomal escape. Here, we establish a combinatorial library composed of 150 molecular weight-defined gemini amphiphiles (GAs) to identify the vehicles that facilitate robust cytosolic delivery of proteins in vitro and in vivo. These GAs display similar skeletal structures but differential amphiphilicity by adjusting the length of alkyl tails, type of ionizable cationic heads, and hydrophobicity or hydrophilicity of a spacer. The top candidate is highly efficient in translocating a broad spectrum of proteins with various molecular weights and isoelectric points into the cytosol. Particularly, we notice that the entry mechanism is predominantly mediated via the lipid raft-dependent membrane fusion, bypassing the classical endocytic pathway that limits the cytosolic delivery efficiency of many presently available carriers. Remarkably, the top GA candidate is capable of delivering hard-to-deliver Cas9 ribonucleoprotein in vivo, disrupting KRAS mutation in the tumor-bearing mice to inhibit tumor growth and extend their survival. Our study reveals a GA-based small-molecule carrier platform for the direct cytosolic delivery of various types of proteins for therapeutic purposes.
研究领域:
药学
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分子生物学
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基因治疗
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癌症研究
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Zhipeng Yang,Haoyuan Li,Biao Yang,Yanjie Liu
Glioblastoma (GBM) is the most common and aggressive malignant brain tumor. Standard therapy includes maximal surgical resection, radiotherapy, and adjuvant temozolomide (TMZ) administration. However, the rapid development of TMZ resistance and the impermeability of the blood–brain barrier (BBB) significantly hinder the therapeutic efficacy. Herein, we developed spatiotemporally controlled microneedle patches (BMNs) loaded with TMZ and niclosamide (NIC) to overcome GBM resistance. We found that hyaluronic acid (HA) increased the viscosity of bovine serum albumin (BSA) and evidenced that concentrations of BSA/HA exert an impact degradation rates exposure to high-temperature treatment, showing that the higher BSA/HA concentrations result in slower drug release. To optimize drug release rates and ensure synergistic antitumor effects, a 15% BSA/HA solution constituting the bottoms of BMNs was chosen to load TMZ, showing sustained drug release for over 28 days, guaranteeing long-term DNA damage in TMZ-resistant cells (U251-TR). Needle tips made from 10% BSA/HA solution loaded with NIC released the drug within 14 days, enhancing TMZ’s efficacy by inhibiting the activity of O6-methylguanine-DNA methyltransferase (MGMT). BMNs exhibit superior mechanical properties, bypass the BBB, and gradually release the drug into the tumor periphery, thus significantly inhibiting tumor proliferation and expanding median survival in mice. The on-demand delivery of BMNs patches shows a strong translational potential for clinical applications, particularly in synergistic GBM treatment.
研究领域:
肿瘤学
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药学
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神经科学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Molecular Cancer
·
2022
·Vol. 21
·期 1
·1-23
·
IF 41.444
Yao Bing,Zhu Sha,Wei Xiyi,Chen Ming-Kun,Feng Yangkun,Li Zhimin,Xu Xinyu,Zhang Yuwei,Wang Yang,Zhou Jingwan,Tang Ningyuan,Ji Chengjian,Jiang Peng,Zhao Shan-Chao,Qin Chao,Feng Ninghan
Background Prostate cancer (PCa) is the most frequently diagnosed malignancy in men, and its mechanism remains poorly understood. Therefore, it is urgent to discover potential novel diagnostic biomarkers and therapeutic targets that can potentially facilitate the development of efficient anticancer strategies.Methods A series of functional in vitro and in vivo experiments were conducted to evaluate the biological behaviors of PCa cells. RNA pulldown, Western blot, luciferase reporter, immunohistochemistry and chromatin immunoprecipitation assays were applied to dissect the detailed underlying mechanisms. High-throughput sequencing was performed to screen for differentially expressed circRNAs in PCa and adjacent normal tissues.Results Upregulation of protein arginine methyltransferase 5 (PRMT5) is associated with poor progression-free survival and the activation of multiple signaling pathways in PCa. PRMT5 inhibits the transcription of CAMK2N1 by depositing the repressive histone marks H4R3me2s and H3R8me2s on the proximal promoter region of CAMK2N1, and results in malignant progression of PCa both in vitro and in vivo. Moreover, the expression of circSPON2, a candidate circRNA in PCa tissues identified by RNA-seq, was found to be associated with poor clinical outcomes in PCa patients. Further results showed that circSPON2 induced PCa cell proliferation and migration, and that the circSPON2-induced effects were counteracted by miR-331-3p. Particularly, circSPON2 acted as a competitive endogenous RNA (ceRNA) of miR-331-3p to attenuate the repressive effects of miR-331-3p on its downstream target PRMT5.Conclusion sOur findings showed that the epigenetic regulator PRMT5 aggravates PCa progression by inhibiting the transcription of CAMK2N1 and is modulated by the circSPON2/miR-331-3p axis, which may serve as a potential therapeutic target for patients with aggressive PCa.
研究领域:
肿瘤学
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分子生物学
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表观遗传学
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癌症生物学
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分子遗传学
✓ 已验证
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2024
·
IF 6.6
Dan Wang,Xiaobo Wang,Yan Li,Xiaowei Wang,Xuelei Wang,Jiayi Su,Apeng Wang,Kai Lv,Mingliang Liu,Guimin Xia
Background Gemcitabine (Gem) is one of the first-line chemotherapy drugs for pancreatic cancer treatment. However, its short half-life in plasma and adverse effects limited its broader application.Methods A novel Gem derivative (N4-tetradecyloxycarbonyl gemcitabine, tcGem) was synthesized and encapsulated into liposomes (LipotcGem) to overcome the above shortcomings.Results LipotcGem has been successfully formulated, with the average size of 115 nm, zeta potential values of −36 mV, encapsulation efficiency of up to 98%, and drug loading capacity of 8.1%. Compared to Gem, LipotcGem improved in vitro antitumor activity significantly, as evidenced by the lower IC50, the higher percentage of apoptotic cells, the stronger ability to inhibit cell migration and invasion due to the higher cellular accumulation (100 times). Additionally, the endocytosis of LipotcGem was mainly mediated by caveolae, and was then processed in the lysosome, where tcGem was released and hydrolyzed into Gem. LipotcGem inhibited tumor growth by 70% in subcutaneous xenograft model and 90% in orthotopic xenograft model, respectively. LipotcGem suppressed tumor metastasis and prolonged survival without perceptible systemic toxicity, which may be caused by the longer t1/2 in vivo (3.5 times, 5.23 vs 1.46 h) and more enrichment in tumor tissue (750 times).Conclusion LipotcGem significantly increased the anti-tumor efficiency and decreased the toxicity for chemotherapy of pancreatic cancer.
研究领域:
肿瘤学
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药学
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药物递送系统
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癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nanomedicine-Nanotechnology Biology and Medicine
·
2022
·
IF 6.458
Zhang Ye,Lun Gao,Jiayang Cai,Yixuan Wang,Yong Li,Shiao Tong,Tengfeng Yan,Qian Sun,Yangzhi Qi,Yang Xu,Hongxiang Jiang,Si Zhang,Linyao Zhao,Shenqi Zhang,Qianxue Chen
Glioblastoma multiforme (GBM) is the intracranial malignancy with the highest rates of morbidity and mortality. Chemotherapy is often ineffective against GBM due to the presence of the blood–brain barrier (BBB); however, the application of nanotechnology is expected to overcome this limitation. Poly(lactic-co-glycolic acid) (PLGA) is a degradable and nontoxic functional polymer with good biocompatibility that is widely used in the pharmaceutical industry. Previous studies have shown that the ability of PLGA nanoparticles (NPs) to penetrate the BBB is largely determined by their size; however, determination of the optimal PLGA NP size requires further research. Here, we report a tandutinib-based prodrug (proTan), which responds to the GBM microenvironment , that was combined with NPs to overcome the BBB. AMD3100-PLGA NPs loaded with proTan inhibited tumor growth and effectively prolonged the survival of tumor-bearing mice.
研究领域:
药学
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纳米技术
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肿瘤学
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神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2022
·Vol. 20
·期 1
·1-20
·
IF 9.429
Zhang Ying,Zhu Jingyao,Zhang Zheng,He Dannong,Zhu Jun,Chen Yunsheng,Zhang Yixin
The anticancer treatment is largely affected by the microenvironment of the tumors, which not only resists the tumors to the thermo/chemo-therapy, but also promotes their growth and invasion. In this work, the angiogenesis factor is balanced by combining with the breathing hyperoxygen, for regulating the tumor microenvironment and also for relieving hypoxia and high tissue interstitial pressure, which promote drug delivery to tumor tissues by increasing the in vivo perfusion and reversing the immunosuppressive tumor. In addition, the designed multifunctional nanoparticles have a great potential for applications to the tumor dual-mode imaging including magnetic resonance (MR) and photoacoustic (PA) imaging. This work proposes a promising strategy to enhance the thermo/chemo-therapy efficacy by remodeling the tumor microenvironment, which would provide an alternative to prolong the lifetime of tumor patients. Graphical Abstract
研究领域:
肿瘤学
·
生物医学工程
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纳米技术
·
成像科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2023
·
IF 17.1
Xianglong Tang,Zhen Wang,Yandong Xie,Yuyang Liu,Kun Yang,Taiping Li,Hong Shen,Mengjie Zhao,Juan Jin,Hong Xiao,Hongyi Liu,Ning Gu
Radiotherapy-resistant glioblastoma (rrGBM) remains a significant clinical challenge because of high infiltrative growth characterized by activation of antiapoptotic signal transduction. Herein, we describe an efficiently biodegradable selenium-engineered mesoporous silica nanocapsule, initiated by high-energy X-ray irradiation and employed for at-site RNA interference (RNAi) to inhibit rrGBM invasion and achieve maximum therapeutic benefit. Our radiation-triggered RNAi nanocapsule showed high physiological stability, good blood-brain barrier transcytosis, and potent rrGBM accumulation. An intratumoral RNAi nanocapsule permitted low-dose X-ray radiation-triggered dissociation for cofilin-1 knockdown, inhibiting rrGBM infiltration. More importantly, tumor suppression was further amplified by electron-affinity aminoimidazole products converted from metronidazole polymers under X-ray radiation-exacerbated hypoxia, which sensitized cell apoptosis to ionizing radiation by fixing reactive oxygen species-induced DNA lesions. In vivo experiments confirmed that our RNAi nanocapsule reduced tumor growth and invasion, prolonging survival in an orthotopic rrGBM model. Generally, we present a promising radiosensitizer that would effectively improve rrGBM-patient outcomes with low-dose X-ray irradiation.
研究领域:
纳米技术
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癌症生物学
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放射生物学
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药学
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神经肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）