Publications by authors named "Chang Zou"

92 Publications

Novel nanomedicines to overcome cancer multidrug resistance.

Drug Resist Updat 2021 Sep 4;58:100777. Epub 2021 Aug 4.

Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518001, Guangdong, PR China; Shenzhen Public Service Platform on Tumor Precision Medicine and Molecular Diagnosis, Shenzhen, 518001, Guangdong, PR China. Electronic address:

Chemotherapy remains a powerful tool to eliminate malignant cells. However, the efficacy of chemotherapy is compromised by the frequent emergence of intrinsic and acquired multidrug resistance (MDR). These chemoresistance modalities are based on a multiplicity of molecular mechanisms of drug resistance, including : 1) Impaired drug uptake into cancer cells; 2) Increased expression of ATP-binding cassette efflux transporters; 3) Loss of function of pro-apoptotic factors; 4) Enhanced DNA repair capacity; 5) Qualitative or quantitative alterations of specific cellular targets; 6) Alterations that allow cancer cells to tolerate adverse or stressful conditions; 7) Increased biotransformation or metabolism of anticancer drugs to less active or completely inactive metabolites; and 8) Intracellular and intercellular drug sequestration in well-defined organelles away from the cellular target. Hence, one of the major aims of cancer research is to develop novel strategies to overcome cancer drug resistance. Over the last decades, nanomedicine, which focuses on targeted delivery of therapeutic drugs into tumor tissues using nano-sized formulations, has emerged as a promising tool for cancer treatment. Therefore, nanomedicine has been introduced as a reliable approach to improve treatment efficacy and minimize detrimental adverse effects as well as overcome cancer drug resistance. With rationally designed strategies including passively targeted delivery, actively targeted delivery, delivery of multidrug combinations, as well as multimodal combination therapy, nanomedicine paves the way towards efficacious cancer treatment and hold great promise in overcoming cancer drug resistance. Herein, we review the recent progress of nanomaterials used in medicine, including liposomal nanoparticles, polymeric nanoparticles, inorganic nanoparticles and hybrid nanoparticles, to surmount cancer multidrug resistance. Finally, the future perspectives of the application of nanomedicine to reverse cancer drug resistance will be addressed.
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http://dx.doi.org/10.1016/j.drup.2021.100777DOI Listing
September 2021

Methyltransferase-like protein 11A promotes migration of cervical cancer cells via up-regulating ELK3.

Pharmacol Res 2021 Oct 25;172:105814. Epub 2021 Aug 25.

Department of Gynaecology, The First Affiliated Hospital of Jinan University, Guangzhou, China. Electronic address:

Cervical cancer is one of the common malignancies in women, which is characterized with high invasion and metastatic tendency in its advanced stage. Increasing evidence indicates that methyltransferase-like (METTL) gene family is involved in the progression of various cancers. However, the functional role of methyltransferase-like gene family in cervical cancer remains unclear. In the present study, we found that METTL11A, a member of the methyltransferase-like gene family, was significantly over-expressed in cervical carcinoma by analyzing TCGA database. This finding was further validated in clinical tissue samples. Moreover, ectopic expression of METTL11A in cervical cancer cell lines promoted cell proliferation and migration both in vitro and in vivo. Differential gene expression analysis in the transcriptomic sequencing data indicated that ELK3 was down-regulated in METTL11A-silenced cervical cancer cells, which was further verified at both protein and mRNA levels. Functional experiments identified that METTL11A promoted migration of cervical cancer cells in an ELK3-dependent manner. This study will promote understanding the mechanism of cervical cancer progression and the functional role of methyltransferase-like gene families in cancers.
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http://dx.doi.org/10.1016/j.phrs.2021.105814DOI Listing
October 2021

Circulating trophoblast cell clusters for early detection of placenta accreta spectrum disorders.

Nat Commun 2021 08 3;12(1):4408. Epub 2021 Aug 3.

Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Placenta accreta spectrum (PAS) is a high-risk obstetrical condition associated with significant morbidity and mortality. Current clinical screening modalities for PAS are not always conclusive. Here, we report a nanostructure-embedded microchip that efficiently enriches both single and clustered circulating trophoblasts (cTBs) from maternal blood for detecting PAS. We discover a uniquely high prevalence of cTB-clusters in PAS and subsequently optimize the device to preserve the intactness of these clusters. Our feasibility study on the enumeration of cTBs and cTB-clusters from 168 pregnant women demonstrates excellent diagnostic performance for distinguishing PAS from non-PAS. A logistic regression model is constructed using a training cohort and then cross-validated and tested using an independent cohort. The combined cTB assay achieves an Area Under ROC Curve of 0.942 (throughout gestation) and 0.924 (early gestation) for distinguishing PAS from non-PAS. Our assay holds the potential to improve current diagnostic modalities for the early detection of PAS.
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http://dx.doi.org/10.1038/s41467-021-24627-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8333096PMC
August 2021

Plasma Levels of Heat Shock Protein 90 Alpha Associated With Colorectal Cancer Development.

Front Mol Biosci 2021 8;8:684836. Epub 2021 Jul 8.

Department of Research, Guangxi Medical University Cancer Hospital, Nanning, China.

The role of plasma heat shock protein 90 alpha (HSP90α) in colorectal cancer patients remains unclear. This study aimed to evaluate the relationship between HSP90α and the occurrence and development of colorectal cancer through diagnosis and prognosis value. 635 colorectal cancer patients and 295 healthy controls were recruited. The HSP90α was measured by using the ELISA kit in all objects and the immune cells and common biomarkers as CEA, AFP, CA125, CA153 and CA199 were measured in all colorectal cancer patients. The relationship between plasma HSP90α with clinical features, common tumor markers and immune cells were also conducted. The survival analysis endpoint was progression-free survival (PFS). The levels of plasma HSP90α were significantly higher in colorectal cancer patients compared to healthy controls [51.4 (ng/ml) vs. 43.7 (ng/ml), < 0.001]. In additional, the levels of plasma HSP90α were associated with gender and disease progress as stage, lymphatic and distant metastasis. Furthermore, plasma HSP90α was closed correlation with CEA, CA125, CA199 and percentage of B cells. However, the initial expression level of plasma HSP90α failed to show a prognostic value for progression-free survival in colorectal cancer. The plasma Hsp90α was remarkable higher in colorectal cancer and correlated with common tumor biomarkers and immune cells. Plasma Hsp90α levels were associated with disease progress but a poor diagnosis performance and also failed to show a prognostic value in colorectal cancer.
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http://dx.doi.org/10.3389/fmolb.2021.684836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8295900PMC
July 2021

Integrative multiplatform-based molecular profiling of human colorectal cancer reveals proteogenomic alterations underlying mitochondrial inactivation.

Am J Cancer Res 2021 15;11(6):2893-2910. Epub 2021 Jun 15.

Department of Clinical Medical Research Center, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital) Shenzhen 518020, China.

Mitochondria play leading roles in initiation and progression of colorectal cancer (CRC). Proteogenomic analyses of mitochondria of CRC tumor cells would likely enhance our understanding of CRC pathogenesis and reveal new independent prognostic factors and treatment targets. However, comprehensive investigations focused on mitochondria of CRC patients are lacking. Here, we investigated global profiles of structural variants, DNA methylation, chromatin accessibility, transcriptome, proteome, and phosphoproteome on human CRC. Proteomic investigations uncovered greatly diminished mitochondrial proteome size in CRC relative to that found in adjacent healthy tissues. Integrated with analysis of RNA-Seq datasets obtained from the public database containing mRNA data of 538 CRC patients, the proteomic analysis indicated that proteins encoded by 45.5% of identified prognostic CRC genes were located within mitochondria, highlighting the association between altered mitochondrial function and CRC. Subsequently, we compared structural variants, DNA methylation, and chromatin accessibility of differentially expressed genes and found that chromatin accessibility was an important factor underlying mitochondrial gene expression. Furthermore, phosphoproteomic profiling demonstrated decreased phosphorylation of most mitochondria-related kinases within CRC versus adjacent healthy tissues, while also highlighting MKK3/p38 as an essential mitochondrial regulatory pathway. Meanwhile, systems-based analyses revealed identities of key kinases, transcriptional factors, and their interconnections. This research uncovered a close relationship between mitochondrial dysfunction and poor CRC prognosis, improve our understanding of molecular mechanism underlying mitochondrial linked to human CRC, and facilitate identifies of clinically relevant CRC prognostic factors and drug targets.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263689PMC
June 2021

Kinectin 1 promotes the growth of triple-negative breast cancer via directly co-activating NF-kappaB/p65 and enhancing its transcriptional activity.

Signal Transduct Target Ther 2021 Jul 5;6(1):250. Epub 2021 Jul 5.

Department of Clinical Medical Research Center, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, PR China.

Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer. Various endeavor has been made to explore the molecular biology basis of TNBC. Herein, we reported a novel function of factor Kinectin 1 (KTN1) as a carcinogenic promoter in TNBC. KTN1 expression in TNBC was increased compared with adjacent tissues or luminal or Her2 subtypes of breast cancer, and TNBC patients with high KTN1 expression have poor prognosis. In functional studies, knockdown of KTN1 inhibited the proliferation and invasiveness of TNBC both in vitro and in vivo, while overexpression of KTN1 promoted cancer cell proliferation and invasiveness. RNA-seq analysis revealed that the interaction of cytokine-cytokine receptor, particularly CXCL8 gene, was upregulated by KTN1, which was supported by the further experiments. CXCL8 depletion inhibited the tumorigenesis and progression of TNBC. Additionally, rescue experiments validated that KTN1-mediated cell growth acceleration in TNBC was dependent on CXCL8 both in vitro and in vivo. Furthermore, it was found that KTN1 enhanced the phosphorylation of NF-κB/p65 protein at Ser536 site, and specifically bound to NF-κB/p65 protein in the nucleus and cytoplasm of cells. Moreover, the transcription of CXCL8 gene was directly upregulated by the complex of KTN1 and NF-κB/p65 protein. Taken together, our results elucidated a novel mechanism of KTN1 gene in TNBC tumorigenesis and progression. KTN1 may be a potential molecular target for the development of TNBC treatment.
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http://dx.doi.org/10.1038/s41392-021-00652-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255318PMC
July 2021

Growth differentiation factor 15 neutralization does not impact anorexia or survival in lipopolysaccharide-induced inflammation.

iScience 2021 Jun 19;24(6):102554. Epub 2021 May 19.

Internal Medicine Research Unit, Pfizer Inc, 1 Portland St, Cambridge, MA 02139, USA.

Growth differentiation factor 15 (GDF15) causes anorexia and weight loss in animal models, and higher circulating levels are associated with cachexia and reduced survival in cancer and other chronic diseases such as sepsis. To investigate the role of sepsis-induced GDF15, we examined whether GDF15 neutralization via a validated and highly potent monoclonal antibody, mAB2, modulates lipopolysaccharide (LPS)-induced anorexia, weight loss, and mortality in rodents. LPS injection transiently increased circulating GDF15 in wild-type mice, decreased food intake and body weight, and increased illness behavior and mortality at a high dose. GDF15 neutralization with mAB2 did not prevent or exacerbate any of the effects of LPS. Similarly, in GDF15 knockout mice, the LPS effect on appetite and survival was comparable with that observed in wild-type controls. Therefore, effective inhibition of circulating active GDF15 via an antibody or via gene knockout demonstrated that survival in the LPS acute inflammation model was independent of GDF15.
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http://dx.doi.org/10.1016/j.isci.2021.102554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215224PMC
June 2021

Multi-omics analyses of human colorectal cancer revealed three mitochondrial genes potentially associated with poor outcomes of patients.

J Transl Med 2021 06 26;19(1):273. Epub 2021 Jun 26.

Department of Clinical Medical Research Center, Guangdong Provincial Engineering Research Center of Autoimmune Disease Precision Medicine, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen, 518020, China.

Background: The identification of novel functional biomarkers is essential for recognizing high-risk patients, predicting recurrence, and searching for appropriate treatment. However, no prognostic biomarker has been applied for colorectal cancer (CRC) in the clinic.

Methods: Integrated with transcriptomic data from public databases, multi-omics examinations were conducted to search prognostic biomarkers for CRC. Moreover, the potential biological functions and regulatory mechanism of these predictive genes were also explored.

Results: In this study, we revealed that three mitochondrial genes were associated with the poor prognosis of CRC. Integrated analyses of transcriptome and proteome of CRC patients disclosed numerous down-regulated mitochondrial genes at both mRNA and protein levels, suggesting a vital role of mitochondria in carcinogenesis. Combined with the bioinformatics studies of transcriptomic datasets of 538 CRC patients, three mitochondrial prognostic genes were eventually selected out, including HIGD1A, SUCLG2, and SLC25A24. The expression of HIGD1A exhibited a significant reduction in two subtypes of adenoma and six subtypes of CRC, while the down-regulation of SUCLG2 and SLC25A24 showed more advantages in rectal mucinous adenocarcinoma. Moreover, we unveiled that these three genes had common expressions and might collaboratively participate in the synthesis of ribosomes. Our original multi-omics datasets, including DNA methylation, structural variants, chromatin accessibility, and phosphoproteome, further depicted the altered modifications on their potential transcriptional factors.

Conclusions: In summary, HIGD1A, SUCLG2, and SLC25A24 might serve as predictive biomarkers for CRC. The biological activities they involved in and their upstream regulators we uncovered would provide a functional context for the further-in-depth mechanism study.
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http://dx.doi.org/10.1186/s12967-021-02939-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8236205PMC
June 2021

Combining the Fecal Immunochemical Test with a Logistic Regression Model for Screening Colorectal Neoplasia.

Front Pharmacol 2021 17;12:635481. Epub 2021 Mar 17.

Department of Health Management, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen People's Hospital, Shenzhen, China.

The fecal immunochemical test (FIT) is a widely used strategy for colorectal cancer (CRC) screening with moderate sensitivity. To further increase the sensitivity of FIT in identifying colorectal neoplasia, in this study, we established a classifier model by combining FIT result and other demographic and clinical features. A total of 4,477 participants were examined with FIT and those who tested positive (over 100 ng/ml) were followed up by a colonoscopy examination. Demographic and clinical information of participants including four domains (basic information, clinical history, diet habits and life styles) that consist of 15 features were retrieved from questionnaire surveys. A mean decrease accuracy (MDA) score was used to select features that are mostly related to CRC. Five different algorithms including logistic regression (LR), classification and regression tree (CART), support vector machine (SVM), artificial neural network (ANN) and random forest (RF) were used to generate a classifier model, through a 10X cross validation process. Area under curve (AUC) and normalized mean squared error (NMSE) were used in the evaluation of the performance of the model. The top six features that are mostly related to CRC include age, gender, history of intestinal adenoma or polyposis, smoking history, gastrointestinal discomfort symptom and fruit eating habit were selected. LR algorithm was used in the generation of the model. An AUC score of 0.92 and an NMSE score of 0.076 were obtained by the final classifier model in separating normal individuals from participants with colorectal neoplasia. Our results provide a new "Funnel" strategy in colorectal neoplasia screening via adding a classifier model filtering step between FIT and colonoscopy examination. This strategy minimizes the need of colonoscopy examination while increases the sensitivity of FIT-based CRC screening.
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http://dx.doi.org/10.3389/fphar.2021.635481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058550PMC
March 2021

A 23-Gene Classifier urine test for prostate cancer prognosis.

Clin Transl Med 2021 03;11(3):e340

Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen Urology Minimally Invasive Engineering Centre, Shenzhen, China.

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http://dx.doi.org/10.1002/ctm2.340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919118PMC
March 2021

Targeting cancer-associated fibroblast-secreted WNT2 restores dendritic cell-mediated antitumour immunity.

Gut 2021 Mar 10. Epub 2021 Mar 10.

Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pharmacology and International Cancer Center, Shenzhen University Health Science Center, Shenzhen, China

Objective: Solid tumours respond poorly to immune checkpoint inhibitor (ICI) therapies. One major therapeutic obstacle is the immunosuppressive tumour microenvironment (TME). Cancer-associated fibroblasts (CAFs) are a key component of the TME and negatively regulate antitumour T-cell response. Here, we aimed to uncover the mechanism underlying CAFs-mediated tumour immune evasion and to develop novel therapeutic strategies targeting CAFs for enhancing ICI efficacy in oesophageal squamous cell carcinoma (OSCC) and colorectal cancer (CRC).

Design: Anti-WNT2 monoclonal antibody (mAb) was used to treat immunocompetent C57BL/6 mice bearing subcutaneously grafted mEC25 or CMT93 alone or combined with anti-programmed cell death protein 1 (PD-1), and the antitumour efficiency and immune response were assessed. CAFs-induced suppression of dendritic cell (DC)-differentiation and DC-mediated antitumour immunity were analysed by interfering with CAFs-derived WNT2, either by anti-WNT2 mAb or with short hairpin RNA-mediated knockdown. The molecular mechanism underlying CAFs-induced DC suppression was further explored by RNA-sequencing and western blot analyses.

Results: A negative correlation between WNT2 CAFs and active CD8 T cells was detected in primary OSCC tumours. Anti-WNT2 mAb significantly restored antitumour T-cell responses within tumours and enhanced the efficacy of anti-PD-1 by increasing active DC in both mouse OSCC and CRC syngeneic tumour models. Directly interfering with CAFs-derived WNT2 restored DC differentiation and DC-mediated antitumour T-cell responses. Mechanistic analyses further demonstrated that CAFs-secreted WNT2 suppresses the DC-mediated antitumour T-cell response via the SOCS3/p-JAK2/p-STAT3 signalling cascades.

Conclusions: CAFs could suppress antitumour immunity through WNT2 secretion. Targeting WNT2 might enhance the ICI efficacy and represent a new anticancer immunotherapy.
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http://dx.doi.org/10.1136/gutjnl-2020-322924DOI Listing
March 2021

Mutational Pattern in Multiple Pulmonary Nodules Are Associated With Early Stage Lung Adenocarcinoma.

Front Oncol 2020 19;10:571521. Epub 2021 Feb 19.

Clinical Medical Research Centre, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen People's Hospital, Shenzhen, China.

The clinical significance of mutation in multiple pulmonary nodules is largely limited by single gene mutation-directed analysis and lack of validation of gene expression profiles. New analytic strategy is urgently needed for comprehensive understanding of genomic data in multiple pulmonary nodules. In this study, we performed whole exome sequencing in 16 multiple lung nodules and 5 adjacent normal tissues from 4 patients with multiple pulmonary nodules and decoded the mutation information from a perspective of cellular functions and signaling pathways. Mutated genes as well as mutation patterns shared in more than two lesions were identified and characterized. We found that the number of mutations or mutated genes and the extent of protein structural changes caused by different mutations is positively correlated with the degree of malignancy. Moreover, the mutated genes in the nodules are associated with the molecular functions or signaling pathways related to cell proliferation and survival. We showed a developing pattern of quantity (the number of mutations/mutated genes) and quality (the extent of protein structural changes) in multiple pulmonary nodules. The mutation and mutated genes in multiple pulmonary nodules are associated with cell proliferation and survival related signaling pathways. This study provides a new perspective for comprehension of genomic mutational data and might shed new light on deciphering molecular evolution of early stage lung adenocarcinoma.
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http://dx.doi.org/10.3389/fonc.2020.571521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934775PMC
February 2021

Establishing a Urine-Based Biomarker Assay for Prostate Cancer Risk Stratification.

Front Cell Dev Biol 2020 10;8:597961. Epub 2020 Dec 10.

Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, Shenzhen, China.

One of the major features of prostate cancer (PCa) is its heterogeneity, which often leads to uncertainty in cancer diagnostics and unnecessary biopsies as well as overtreatment of the disease. Novel non-invasive tests using multiple biomarkers that can identify clinically high-risk cancer patients for immediate treatment and monitor patients with low-risk cancer for active surveillance are urgently needed to improve treatment decision and cancer management. In this study, we identified 14 promising biomarkers associated with PCa and tested the performance of these biomarkers on tissue specimens and pre-biopsy urinary sediments. These biomarkers showed differential gene expression in higher- and lower-risk PCa. The 14-Gene Panel urine test (, , , , , , , , , , , , , and ) was assessed in two independent prospective and retrospective urine study cohorts and showed high diagnostic accuracy to identify higher-risk PCa patients with the need for treatment and lower-risk patients for surveillance. The AUC was 0.897 (95% CI 0.939-0.855) in the prospective cohort ( = 202), and AUC was 0.899 (95% CI 0.964-0.834) in the retrospective cohort ( = 97). In contrast, serum PSA and Gleason score had much lower accuracy in the same 202 patient cohorts [AUC was 0.821 (95% CI 0.879-0.763) for PSA and 0.860 (95% CI 0.910-0.810) for Gleason score]. In addition, the 14-Gene Panel was more accurate at risk stratification in a subgroup of patients with Gleason scores 6 and 7 in the prospective cohort ( = 132) with AUC of 0.923 (95% CI 0.968-0.878) than PSA [AUC of 0.773 (95% CI 0.852-0.794)] and Gleason score [AUC of 0.776 (95% CI 0.854-0.698)]. Furthermore, the 14-Gene Panel was found to be able to accurately distinguish PCa from benign prostate with AUC of 0.854 (95% CI 0.892-0.816) in a prospective urine study cohort ( = 393), while PSA had lower accuracy with AUC of 0.652 (95% CI 0.706-0.598). Taken together, the 14-Gene Panel urine test represents a promising non-invasive tool for detection of higher-risk PCa to aid treatment decision and lower-risk PCa for active surveillance.
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http://dx.doi.org/10.3389/fcell.2020.597961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758396PMC
December 2020

Comprehensive assessment of PD-L1 and PD-L2 dysregulation in gastrointestinal cancers.

Epigenomics 2020 12 18;12(24):2155-2171. Epub 2020 Dec 18.

Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, PR China.

and are ligands of . Their overexpression has been reported in different cancers. However, the underlying mechanism of and dysregulation and their related signaling pathways are still unclear in gastrointestinal cancers. The expression of and were studied in The Cancer Genome Atlas and Genotype-Tissue Expression databases. The gene and protein alteration of and were analyzed in cBioportal. The direct transcription factor regulating / was determined with ChIP-seq data. The association of expression with clinicopathological parameters, survival, immune infiltration and tumor mutation burden were investigated with data from The Cancer Genome Atlas. Potential targets and pathways of and were determined by protein enrichment, WebGestalt and gene ontology. Comprehensive analysis revealed that and were significantly upregulated in most types of gastrointestinal cancers and their expressions were positively correlated. was a key transcription factor regulating the expression of . Higher or expression was significantly associated with poor overall survival, higher tumor mutation burden and more immune and stromal cell populations. Finally, HIF-1, ERBB and mTOR signaling pathways were most significantly affected by and dysregulation. Altogether, this study provided comprehensive analysis of the dysregulation of and , its underlying mechanism and downstream pathways, which add to the knowledge of manipulating for cancer immunotherapy.
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http://dx.doi.org/10.2217/epi-2020-0093DOI Listing
December 2020

The Stoppa combined with iliac fossa approach for the treatment of both-column acetabular fractures.

J Orthop Surg Res 2020 Dec 7;15(1):588. Epub 2020 Dec 7.

Department of Orthopaedics, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.

Background: At present, the choice of surgical approach for both-column fractures is still controversial. The purpose of this study was to explore the efficacy of the Stoppa combined with iliac fossa (S+IF) approach in the treatment of both-column fractures.

Methods: In this retrospective case series, 76 patients were included in the study from 2014 to 2018. They were divided into two groups according to the surgical approaches. The differences of intraoperative blood loss, operative time, quality of reduction, clinical outcome, and perioperative complications were compared between the two groups.

Results: All patients had undergone the IL approach or the S+IF approach. The average operative time was 156.2 min (110~210 min) in group I and 126.5 min (80~180 min) in group II (P < 0.001). The average blood loss in group I was 784.1 ml, while the average blood loss in group II was 625.3 ml (P = 0.007). According to Matta's criteria, 28 cases obtained anatomic reduction and 12 cases got imperfect reduction in group I; 21 cases obtained anatomic reduction and 7 cases got imperfect reduction in group II (P > 0.05). The clinical outcome (excellent to good) was 66% in group I versus 69% in group II (P > 0.05). The complication rates were 18.2% in group I and 12.5% in group II (P > 0.05).

Conclusions: As a minimally invasive surgical approach, the S+IF approach is a valuable alternative to the IL approach for the treatment of both-column acetabular fractures if these two anterior approaches can achieve fracture exposure, reduction, and fixation.
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http://dx.doi.org/10.1186/s13018-020-02133-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720542PMC
December 2020

Target Profiling of an Anticancer Drug Curcumin by an In Situ Chemical Proteomics Approach.

Methods Mol Biol 2021 ;2213:147-161

Institute of Chinese Materia Medica, and Artemisinin Research Center, China Academy of Chinese Medical Sciences, Beijing, China.

Interdisciplinary chemical proteomics approaches have been widely applied to the identification of specific targets of bioactive small molecules or drugs. In this chapter, we describe the application of a cell-permeable activity-based curcumin probe (Cur-P) with an alkyne moiety to detect and identify specific binding targets of curcumin in HCT116 colon cancer cells. Through click chemistry, a fluorescent tag or a biotin tag is attached to the probe-modified curcumin targets for visualization or affinity purification followed by mass spectrometric identification. A quantitative proteomics approach of isobaric tags for relative and absolute quantification (iTRAQ)™ is applied to distinguish specific curcumin targets from nonspecific binding proteins.
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http://dx.doi.org/10.1007/978-1-0716-0954-5_13DOI Listing
March 2021

Development and validation of a 25-Gene Panel urine test for prostate cancer diagnosis and potential treatment follow-up.

BMC Med 2020 12 1;18(1):376. Epub 2020 Dec 1.

Department of Urology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, Guangdong, China.

Background: Heterogeneity of prostate cancer (PCa) contributes to inaccurate cancer screening and diagnosis, unnecessary biopsies, and overtreatment. We intended to develop non-invasive urine tests for accurate PCa diagnosis to avoid unnecessary biopsies.

Methods: Using a machine learning program, we identified a 25-Gene Panel classifier for distinguishing PCa and benign prostate. A non-invasive test using pre-biopsy urine samples collected without digital rectal examination (DRE) was used to measure gene expression of the panel using cDNA preamplification followed by real-time qRT-PCR. The 25-Gene Panel urine test was validated in independent multi-center retrospective and prospective studies. The diagnostic performance of the test was assessed against the pathological diagnosis from biopsy by discriminant analysis. Uni- and multivariate logistic regression analysis was performed to assess its diagnostic improvement over PSA and risk factors. In addition, the 25-Gene Panel urine test was used to identify clinically significant PCa. Furthermore, the 25-Gene Panel urine test was assessed in a subset of patients to examine if cancer was detected after prostatectomy.

Results: The 25-Gene Panel urine test accurately detected cancer and benign prostate with AUC of 0.946 (95% CI 0.963-0.929) in the retrospective cohort (n = 614), AUC of 0.901 (0.929-0.873) in the prospective cohort (n = 396), and AUC of 0.936 (0.956-0.916) in the large combination cohort (n = 1010). It greatly improved diagnostic accuracy over PSA and risk factors (p < 0.0001). When it was combined with PSA, the AUC increased to 0.961 (0.980-0.942). Importantly, the 25-Gene Panel urine test was able to accurately identify clinically significant and insignificant PCa with AUC of 0.928 (95% CI 0.947-0.909) in the combination cohort (n = 727). In addition, it was able to show the absence of cancer after prostatectomy with high accuracy.

Conclusions: The 25-Gene Panel urine test is the first highly accurate and non-invasive liquid biopsy method without DRE for PCa diagnosis. In clinical practice, it may be used for identifying patients in need of biopsy for cancer diagnosis and patients with clinically significant cancer for immediate treatment, and potentially assisting cancer treatment follow-up.
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http://dx.doi.org/10.1186/s12916-020-01834-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706045PMC
December 2020

Editorial: Impact of Cancer Plasticity on Drug Resistance and Treatment in Solid Tumors.

Front Oncol 2020 23;10:596963. Epub 2020 Oct 23.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.

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http://dx.doi.org/10.3389/fonc.2020.596963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649785PMC
October 2020

Supramolecular nanosubstrate-mediated delivery system enables CRISPR-Cas9 knockin of hemoglobin beta gene for hemoglobinopathies.

Sci Adv 2020 Oct 23;6(43). Epub 2020 Oct 23.

Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging (CIMI), California NanoSystems Institute (CNSI), University of California, Los Angeles, Los Angeles, CA 90095, USA.

Leveraging the endogenous homology-directed repair (HDR) pathway, the CRISPR-Cas9 gene-editing system can be applied to knock in a therapeutic gene at a designated site in the genome, offering a general therapeutic solution for treating genetic diseases such as hemoglobinopathies. Here, a combined supramolecular nanoparticle (SMNP)/supramolecular nanosubstrate-mediated delivery (SNSMD) strategy is used to facilitate CRISPR-Cas9 knockin of the hemoglobin beta (HBB) gene into the adeno-associated virus integration site 1 (AAVS1) safe-harbor site of an engineered K562 3.21 cell line harboring the sickle cell disease mutation. Through stepwise treatments of the two SMNP vectors encapsulating a Cas9•single-guide RNA (sgRNA) complex and an HBB/green fluorescent protein (GFP)-encoding plasmid, CRISPR-Cas9 knockin was successfully achieved via HDR. Last, the HBB/GFP-knockin K562 3.21 cells were introduced into mice via intraperitoneal injection to show their in vivo proliferative potential. This proof-of-concept demonstration paves the way for general gene therapeutic solutions for treating hemoglobinopathies.
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http://dx.doi.org/10.1126/sciadv.abb7107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608838PMC
October 2020

Identification of a distinct luminal subgroup diagnosing and stratifying early stage prostate cancer by tissue-based single-cell RNA sequencing.

Mol Cancer 2020 10 8;19(1):147. Epub 2020 Oct 8.

Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China.

Background: The highly intra-tumoral heterogeneity and complex cell origination of prostate cancer greatly limits the utility of traditional bulk RNA sequencing in finding better biomarker for disease diagnosis and stratification. Tissue specimens based single-cell RNA sequencing holds great promise for identification of novel biomarkers. However, this technique has yet been used in the study of prostate cancer heterogeneity.

Methods: Cell types and the corresponding marker genes were identified by single-cell RNA sequencing. Malignant states of different clusters were evaluated by copy number variation analysis and differentially expressed genes of pseudo-bulks sequencing. Diagnosis and stratification of prostate cancer was estimated by receiver operating characteristic curves of marker genes. Expression characteristics of marker genes were verified by immunostaining.

Results: Fifteen cell groups including three luminal clusters with different expression profiles were identified in prostate cancer tissues. The luminal cluster with the highest copy number variation level and marker genes enriched in prostate cancer-related metabolic processes was considered the malignant cluster. This cluster contained a distinct subgroup with high expression level of prostate cancer biomarkers and a strong distinguishing ability of normal and cancerous prostates across different pathology grading. In addition, we identified another marker gene, Hepsin (HPN), with a 0.930 area under the curve score distinguishing normal tissue from prostate cancer lesion. This finding was further validated by immunostaining of HPN in prostate cancer tissue array.

Conclusion: Our findings provide a valuable resource for interpreting tumor heterogeneity in prostate cancer, and a novel candidate marker for prostate cancer management.
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http://dx.doi.org/10.1186/s12943-020-01264-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545561PMC
October 2020

Chloroquine against malaria, cancers and viral diseases.

Drug Discov Today 2020 Sep 16. Epub 2020 Sep 16.

Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, PR China; Guangzhou Institute of Pediatrics/Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, 510623, PR China; The First Affiliated Hospital, Hainan Medical University, Haikou, 571199, PR China. Electronic address:

Quinoline (QN) derivatives are often used for the prophylaxis and treatment of malaria. Chloroquine (CQ), a protonated, weakly basic drug, exerts its antimalarial effect mainly by increasing pH and accumulating in the food vacuole of the parasites. Repurposing CQ is an emerging strategy for new indications. Given the inhibition of autophagy and its immunomodulatory action, CQ shows positive efficacy against cancer and viral diseases, including Coronavirus 2019 (COVID-19). Here, we review the underlying mechanisms behind the antimalarial, anticancer and antiviral effects of CQ. We also discuss the clinical evidence for the use of CQ and hydroxychloroquine (HCQ) against COVID-19.
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http://dx.doi.org/10.1016/j.drudis.2020.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492153PMC
September 2020

Chloroquine and hydroxychloroquine in the treatment of malaria and repurposing in treating COVID-19.

Pharmacol Ther 2020 12 8;216:107672. Epub 2020 Sep 8.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA. Electronic address:

Chloroquine (CQ) and Hydroxychloroquine (HCQ) have been commonly used for the treatment and prevention of malaria, and the treatment of autoimmune diseases for several decades. As their new mechanisms of actions are identified in recent years, CQ and HCQ have wider therapeutic applications, one of which is to treat viral infectious diseases. Since the pandemic of the coronavirus disease 2019 (COVID-19), CQ and HCQ have been subjected to a number of in vitro and in vivo tests, and their therapeutic prospects for COVID-19 have been proposed. In this article, the applications and mechanisms of action of CQ and HCQ in their conventional fields of anti-malaria and anti-rheumatism, as well as their repurposing prospects in anti-virus are reviewed. The current trials and future potential of CQ and HCQ in combating COVID-19 are discussed.
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http://dx.doi.org/10.1016/j.pharmthera.2020.107672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476892PMC
December 2020

Epitranscriptomics and epiproteomics in cancer drug resistance: therapeutic implications.

Signal Transduct Target Ther 2020 09 8;5(1):193. Epub 2020 Sep 8.

Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518001, Guangdong, China.

Drug resistance is a major hurdle in cancer treatment and a key cause of poor prognosis. Epitranscriptomics and epiproteomics are crucial in cell proliferation, migration, invasion, and epithelial-mesenchymal transition. In recent years, epitranscriptomic and epiproteomic modification has been investigated on their roles in overcoming drug resistance. In this review article, we summarized the recent progress in overcoming cancer drug resistance in three novel aspects: (i) mRNA modification, which includes alternative splicing, A-to-I modification and mRNA methylation; (ii) noncoding RNAs modification, which involves miRNAs, lncRNAs, and circRNAs; and (iii) posttranslational modification on molecules encompasses drug inactivation/efflux, drug target modifications, DNA damage repair, cell death resistance, EMT, and metastasis. In addition, we discussed the therapeutic implications of targeting some classical chemotherapeutic drugs such as cisplatin, 5-fluorouridine, and gefitinib via these modifications. Taken together, this review highlights the importance of epitranscriptomic and epiproteomic modification in cancer drug resistance and provides new insights on potential therapeutic targets to reverse cancer drug resistance.
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http://dx.doi.org/10.1038/s41392-020-00300-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479143PMC
September 2020

mA RNA modification modulates PI3K/Akt/mTOR signal pathway in Gastrointestinal Cancer.

Theranostics 2020 25;10(21):9528-9543. Epub 2020 Jul 25.

Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, Sichuan, PR China.

Methylation at the N6 position of adenosine (mA) is the most prevalent RNA modification within protein-coding mRNAs in mammals, and it is a reversible modification with various important biological functions. The formation and function of mA are regulated by methyltransferases (writers), demethylases (erasers), and special binding proteins (readers) as key factors. However, the underlying modification mechanisms of mA in gastrointestinal (GI) cancer remain unclear. Here, we performed comprehensive molecular profiling of the nine known mA writer, eraser, and reader proteins in GI cancer. Data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were used. Gene alteration and pathway analysis were done in cBioportal. The protein network of mA regulators and its related pathway members was analyzed in STRING online platform. Phylogenetic tree was constructed in MEGA7. mA modification sites were predicted by SRAMP. mA related SNPs were analyzed by mASNP. The modulation of mA on its related pathway members was validated by mA-seq, real-time PCR and phosphor-MAPK array. We found that mA regulators were mostly upregulated in GI cancer and their differential expression significantly influenced the overall survival of patients with GI cancer. The phosphatidylinositol-3-kinase (PI3K)/Akt and mammalian target of rapamycin (mTOR) signaling pathways were found to be potentially affected by mA modification in most human cancers, including GI cancer, which was further verified by mA-Seq and phospho-MAPK array. Our findings suggest that mA RNA modification has a fundamental role in the regulation of PI3K/Akt and mTOR signaling pathway function in cancer.
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http://dx.doi.org/10.7150/thno.42971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449908PMC
June 2021

WNT2-Mediated FZD2 Stabilization Regulates Esophageal Cancer Metastasis via STAT3 Signaling.

Front Oncol 2020 16;10:1168. Epub 2020 Jul 16.

Key Laboratory of Digestive Pathophysiology of Zhejiang Province, First Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, China.

Esophageal cancer micro environment factor WNT2 was critical in cancer metastasis. However, very little is known about WNT2 receptors and their role in the malignant progression of ESCC. The clinical significance and underlying molecular mechanisms of FZD2, one of the receptors of WNT2, was further investigated in ESCC. We found that FZD2 expression was positively correlated with WNT2 levels in clinical ESCC specimens through database analysis. Upregulated FZD2 expression was detected in 69% (69/100) of the primary ESCC cases examined, and increased FZD2 expression was significantly correlated with poor prognosis ( < 0.05). Mechanistically, FZD2 induced the migration and invasion of ESCC cells by regulating the FZD2/STAT3 signaling. xenograft experiments further revealed the metastasis-promoting role of FZD2 in ESCC. Moreover, we found that the WNT2 ligand could stabilize and phosphorylate the FZD2 receptor by attenuating FZD2 ubiquitination, leading to the activation of STAT3 signaling and the initiation of ESCC cell metastasis. Collectively, our data revealed that a novel non-canonical WNT2/FZD2/STAT3 signaling axis is critical for ESCC progression. Strategies targeting this specific signaling axis might be developed to treat patients with ESCC.
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http://dx.doi.org/10.3389/fonc.2020.01168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379028PMC
July 2020

Modulation of MnSOD and FoxM1 Is Involved in Invasion and EMT Suppression by Isovitexin in Hepatocellular Carcinoma Cells.

Cancer Manag Res 2020 14;12:5759-5771. Epub 2020 Jul 14.

The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Medical College, Hunan Normal University, Changsha 410013, People's Republic of China.

Background: Manganese superoxide dismutase (MnSOD) induces FoxM1 expression, subsequently contributing to migration in several cancer cells. Isovitexin (ISOV) was recently found to downregulate MnSOD and FoxM1, decreasing stemness in hepatocellular carcinoma (HCC) stem-like cells (HCSLCs). The current study aimed to determine whether inhibition of migration, invasion and EMT in HCSLCs by ISOV results from MnSOD/FoxM1 signaling blockade and subsequent Twist1, Slug, ZEB1 and MMP-2 downregulation.

Materials And Methods: We examined the migratory and invasive capabilities and EMT phenotype in HCC cells and their HCSLCs, respectively, by wound-healing assay, transwell invasion assay and Western blot after treatment with non-cytotoxic concentrations of ISOV, and explored the mechanism by which ISOV affects migration, invasion and EMT by MnSOD or FoxM1 knockdown and/or overexpression in HCSLCs or HCC cells.

Results: The results showed that ISOV not only downregulated MnSOD and FoxM1 but also suppressed the migratory and invasive capabilities and reversed the EMT phenotype in HCSLCs, which was reflected by elevated E-cadherin protein amounts, and reduced N-cadherin, Twist1, Slug, ZEB1 and MMP-2 protein levels. The suppressive effects of ISOV on the migratory and invasive capabilities and EMT phenotype could be potentiated by MnSOD or FoxM1 knockdown in HCSLCs, and attenuated by MnSOD or FoxM1 overexpression in HCC cells. Importantly, FoxM1 overexpression reversed MnSOD knockdown combined with ISOV suppression on the migratory and invasive capabilities and EMT phenotype in HCSLCs, while having little effects on MnSOD expression.

Conclusion: Collectively, the above findings demonstrated that ISOV suppresses migration, invasion and EMT in HCSLCs by blocking MnSOD/FoxM1 signaling subsequently inhibiting the expression of EMT-related transcription factors and MMP-2.
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http://dx.doi.org/10.2147/CMAR.S245283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371559PMC
July 2020

Identifying potential serum biomarkers of breast cancer through targeted free fatty acid profiles screening based on a GC-MS platform.

Biomed Chromatogr 2020 Oct 2;34(10):e4922. Epub 2020 Jul 2.

Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pharmacology and Shenzhen University International Cancer Center, Shenzhen University School of Medicine, Shenzhen, China.

Recent advances suggest that abnormal fatty acid metabolism highly correlates with breast cancer, which provide clues to discover potential biomarkers of breast cancer. This study aims to identify serum free fatty acid (FFA) metabolic profiles and screen potential biomarkers for breast cancer diagnosis. Gas chromatography-mass spectrometry and our in-house fatty acid methyl ester standard substances library were combined to accurately identify FFA profiles in serum samples of breast cancer patients and breast adenosis patients (as controls). Potential biomarkers were screened by applying statistical analysis. A total of 18 FFAs were accurately identified in serum sample. Two groups of patients were correctly discriminated by the orthogonal partial least squares-discriminant analysis model based on FFA profiles. Seven FFA levels were significantly higher in serum from breast cancer patients than that in controls, and exhibited positive correlation with malignant degrees of disease. Furthermore, five candidates (palmitic acid, oleic acid, cis-8,11,14-eicosatrienoic acid, docosanoic acid and the ratio of oleic acid to stearic acid) were selected as potential serum biomarkers for differential diagnosis of breast cancer. Our study will help to reveal the metabolic signature of FFAs in breast cancer patients, and provides valuable information for facilitating clinical noninvasive diagnosis.
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http://dx.doi.org/10.1002/bmc.4922DOI Listing
October 2020

Dual TTK/CLK2 inhibitor, CC-671, selectively antagonizes ABCG2-mediated multidrug resistance in lung cancer cells.

Cancer Sci 2020 Aug 29;111(8):2872-2882. Epub 2020 Jun 29.

Shenzhen People's Hospital, The First Affiliated Hospital of Southern University of Science and Technology, The Second Clinical Medical College of Jinan University, Shenzhen, China.

One pivotal factor that leads to multidrug resistance (MDR) is the overexpression of ABCG2. Therefore, tremendous effort has been devoted to the search of effective reversal agents to overcome ABCG2-mediated MDR. CC-671 is a potent and selective inhibitor of both TTK (human protein kinase monopolar spindle 1 [hMps1]) and CDC like kinase 2 (CLK2). It represents a new class of cancer therapeutic drugs. In this study, we show that CC-671 is an effective ABCG2 reversal agent that enhances the efficacy of chemotherapeutic drugs in ABCG2-overexpressing lung cancer cells. Mechanistic studies show that the reversal effect of CC-671 is primarily attributed to the inhibition of the drug efflux activity of ABCG2, which leads to an increased intracellular level of chemotherapeutic drugs. In addition, CC-671 does not alter the protein expression or subcellular localization of ABCG2. The computational molecule docking analysis suggests CC-671 has high binding affinity to the drug-binding site of ABCG2. In conclusion, we reveal the interaction between CC-671 and ABCG2, providing a rationale for the potential combined use of CC-671 with ABCG2 substrate to overcome MDR.
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http://dx.doi.org/10.1111/cas.14505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419038PMC
August 2020

M3814, a DNA-PK Inhibitor, Modulates ABCG2-Mediated Multidrug Resistance in Lung Cancer Cells.

Front Oncol 2020 12;10:674. Epub 2020 May 12.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States.

M3814, also known as nedisertib, is a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor under phase 2 clinical trials. ABCG2 is a member of the ATP-binding cassette (ABC) transporter family that is closely related to multidrug resistance (MDR) in cancer treatment. In this study, we demonstrated that M3814 can modulate the function of ABCG2 and overcome ABCG2-mediated MDR. Mechanistic studies showed that M3814 can attenuate the efflux activity of ABCG2 transporter, leading to increased ABCG2 substrate drugs accumulation. Furthermore, M3814 can stimulate the ABCG2 ATPase activity in a concentration-dependent manner without affecting the ABCG2 protein expression or cell surface localization of ABCG2. Moreover, the molecular docking analysis indicated a high affinity between M3814 and ABCG2 transporter at the drug-binding cavity. Taken together, our work reveals M3814 as an ABCG2 modulator and provides a potential combination of co-administering M3814 with ABCG2 substrate-drugs to overcome MDR.
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http://dx.doi.org/10.3389/fonc.2020.00674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235170PMC
May 2020

Targeting CLK3 inhibits the progression of cholangiocarcinoma by reprogramming nucleotide metabolism.

J Exp Med 2020 08;217(8)

The Affiliated Hospital of Guilin Medical University, Guangxi Key Laboratory of Brain and Cognitive Neuroscience, Guangxi Neurological Diseases Clinical Research Center, Guilin, Guangxi, China.

CDC-like kinase 3 (CLK3) is a dual specificity kinase that functions on substrates containing serine/threonine and tyrosine. But its role in human cancer remains unknown. Herein, we demonstrated that CLK3 was significantly up-regulated in cholangiocarcinoma (CCA) and identified a recurrent Q607R somatic substitution that represented a gain-of-function mutation in the CLK3 kinase domain. Gene ontology term enrichment suggested that high CLK3 expression in CCA patients mainly was associated with nucleotide metabolism reprogramming, which was further confirmed by comparing metabolic profiling of CCA cells. CLK3 directly phosphorylated USP13 at Y708, which promoted its binding to c-Myc, thereby preventing Fbxl14-mediated c-Myc ubiquitination and activating the transcription of purine metabolic genes. Notably, the CCA-associated CLK3-Q607R mutant induced USP13-Y708 phosphorylation and enhanced the activity of c-Myc. In turn, c-Myc transcriptionally up-regulated CLK3. Finally, we identified tacrine hydrochloride as a potential drug to inhibit aberrant CLK3-induced CCA. These findings demonstrate that CLK3 plays a crucial role in CCA purine metabolism, suggesting a potential therapeutic utility.
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http://dx.doi.org/10.1084/jem.20191779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398168PMC
August 2020
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