Publications by authors named "Hongjuan Cui"

161 Publications

Competing Endogenous RNA Networks in Glioma.

Front Genet 2021 29;12:675498. Epub 2021 Apr 29.

State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.

Gliomas are the most common and malignant primary brain tumors. Various hallmarks of glioma, including sustained proliferation, migration, invasion, heterogeneity, radio- and chemo-resistance, contribute to the dismal prognosis of patients with high-grade glioma. Dysregulation of cancer driver genes is a leading cause for these glioma hallmarks. In recent years, a new mechanism of post-transcriptional gene regulation was proposed, i.e., "competing endogenous RNA (ceRNA)." Long non-coding RNAs, circular RNAs, and transcribed pseudogenes act as ceRNAs to regulate the expression of related genes by sponging the shared microRNAs. Moreover, coding RNA can also exert a regulatory role, independent of its protein coding function, through the ceRNA mechanism. In the latest glioma research, various studies have reported that dysregulation of certain ceRNA regulatory networks (ceRNETs) accounts for the abnormal expression of cancer driver genes and the establishment of glioma hallmarks. These achievements open up new avenues to better understand the hidden aspects of gliomas and provide new biomarkers and potential efficient targets for glioma treatment. In this review, we summarize the existing knowledge about the concept and logic of ceRNET and highlight the emerging roles of some recently found ceRNETs in glioma progression.
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http://dx.doi.org/10.3389/fgene.2021.675498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117106PMC
April 2021

MnO-capped silk fibroin (SF) nanoparticles with chlorin e6 (Ce6) encapsulation for augmented photo-driven therapy by modulating the tumor microenvironment.

J Mater Chem B 2021 05;9(17):3677-3688

State Key Laboratory of Silkworm Genome Biology, School of Materials and Energy, Southwest University, Chongqing 400715, China.

Silk fibroin (SF), derived from Bombyx mori, is a category of fibrous protein with outstanding potential for applications in the biomedical and biotechnological fields. In spite of its many advantageous properties, the exploration of SF as a versatile nanodrug precursor for tumor therapy has still been restricted in recent years. Herein, a multifunctional SF-derived nanoplatform was facilely developed via encapsulating the photosensitizer chlorin e6 (Ce6) into MnO2-capped SF nanoparticles (NPs). [email protected] nanocarriers were synthesized through a surface crystallization technique, using SF as a reductant and sacrificial template. Afterwards, Ce6 was covalently incorporated into the loose structure of the [email protected] nanocarrier on the basis of adsorption to abundant peptide-binding sites. To modulate the tumor microenvironment (TME), [email protected]/Ce6 (SMC) NPs were capable of catalyzing the decomposition of H2O2 into O2, which can be converted into cytotoxic reactive oxygen species (ROS) during photodynamic therapy (PDT). Moreover, the MnO2 component was able to oxidize intracellular glutathione (GSH) into non-reducing glutathione disulfide (GSSG), and the consumption of GSH could significantly protect the local ROS from being reduced, which further augmented the therapeutic outcome of PDT. Via another angle, SMC NPs can produce strong hyperthermia under near-infrared (NIR) light activation, which was highly desirable for efficient photothermal therapy (PTT). Both in vitro and in vivo studies demonstrated the intense tumor inhibitory effects as a result of augmented PTT/PDT mediated by SMC NPs. We believe that this study may provide useful insights for employing SF-based nanocomposites for more medical applications in the near future.
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http://dx.doi.org/10.1039/d1tb00296aDOI Listing
May 2021

Lycorine hydrochloride inhibits melanoma cell proliferation, migration and invasion via down-regulating p21.

Am J Cancer Res 2021 15;11(4):1391-1409. Epub 2021 Apr 15.

State Key Laboratory of Silkworm Genome Biology, Southwest University Chongqing 400715, China.

Lycorine hydrochloride (LH) is an active ingredient sourced from the medicinal herb . Previous studies have suggested that LH exerts tumor suppression activity in several human cancers. However, the anti-cancer effect of LH in melanoma and the potential molecular mechanisms still need to be further studied. p21, unlike its traditional cyclin-dependent kinase (CDK) inhibitor role, is believed to act as an oncogene under certain cellular conditions. In this research, an increased expression of p21 was found in human melanoma tissues and positively related to the tumor invasion depth. High level of p21 was found to correlate with bad outcomes of melanoma patients by Kaplan-Meier survival analysis. Functional experiments demonstrated that the proliferation, migration and invasion ability of A375 and MV3 melanoma cells was powerfully inhibited by LH through inducing S phase cell cycle arrest and regulating epithelial-mesenchymal transition (EMT). In NOD/SCID mice model, LH effectively inhibited the xenograft tumor growth and lung metastasis of A375 cells. Further research revealed that LH reduced p21 protein by accelerating its ubiquitination. Importantly, the LH-induced suppression of cell proliferation and metastasis was rescued by p21 overexpression, both in vitro an in vivo. Taken together, LH, which suppresses the proliferation and metastasis of melanoma cells via down-regulating p21, is expected to be developed as an effective medicine for melanoma therapy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085853PMC
April 2021

POU2F2 regulates glycolytic reprogramming and glioblastoma progression via PDPK1-dependent activation of PI3K/AKT/mTOR pathway.

Cell Death Dis 2021 Apr 30;12(5):433. Epub 2021 Apr 30.

State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.

The POU Class Homeobox 2 (POU2F2) is a member of POU transcription factors family, which involves in cell immune response by regulating B cell proliferation and differentiation genes. Recent studies have shown that POU2F2 acts as tumor-promoting roles in some cancers, but the underlying mechanism remains little known. Here, we identified that the highly expressed POU2F2 significantly correlated with poor prognosis of glioblastoma (GBM) patients. POU2F2 promoted cell proliferation and regulated glycolytic reprogramming. Mechanistically, the AKT/mTOR signaling pathway played important roles in the regulation of POU2F2-mediated aerobic glycolysis and cell growth. Furthermore, we demonstrated that POU2F2 activated the transcription of PDPK1 by directly binding to its promoter. Reconstituted the expression of PDPK1 in POU2F2-knockdown GBM cells reactivated AKT/mTOR pathway and recovered cell glycolysis and proliferation, whereas this effect was abolished by the PDPK1/AKT interaction inhibitor. In addition, we showed that POU2F2-PDPK1 axis promoted tumorigenesis by regulating glycolysis in vivo. In conclusion, our findings indicate that POU2F2 leads a metabolic shift towards aerobic glycolysis and promotes GBM progression in PDPK1-dependent activation of PI3K/AKT/mTOR pathway.
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http://dx.doi.org/10.1038/s41419-021-03719-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087798PMC
April 2021

Overcoming TRAIL Resistance for Glioblastoma Treatment.

Biomolecules 2021 Apr 14;11(4). Epub 2021 Apr 14.

Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China.

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) shows a promising therapeutic potential in cancer treatment as it exclusively causes apoptosis in a broad spectrum of cancer cells through triggering the extrinsic apoptosis pathway via binding to cognate death receptors, with negligible toxicity in normal cells. However, most cancers, including glioblastoma multiforme (GBM), display TRAIL resistance, hindering its application in clinical practice. Recent studies have unraveled novel mechanisms in regulating TRAIL-induced apoptosis in GBM and sought effective combinatorial modalities to sensitize GBM to TRAIL treatment, establishing pre-clinical foundations and the reasonable expectation that the TRAIL/TRAIL death receptor axis could be harnessed to treat GBM. In this review, we will revisit the status quo of the mechanisms of TRAIL resistance and emerging strategies for sensitizing GBM to TRAIL-induced apoptosis and also discuss opportunities of TRAIL-based combinatorial therapies in future clinical use for GBM treatment.
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http://dx.doi.org/10.3390/biom11040572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070820PMC
April 2021

Polydatin Inhibits Cell Viability, Migration, and Invasion Through Suppressing the c-Myc Expression in Human Cervical Cancer.

Front Cell Dev Biol 2021 12;9:587218. Epub 2021 Apr 12.

State Key Laboratory of Silkworm Genome Biology, College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing, China.

Polydatin, an active ingredient from the roots of , is considered to have protective effects on the cardiovascular system and liver. In this study, we demonstrated that polydatin has antitumor activity against human cervical cancer. Polydatin efficiently inhibited cervical cancer cell proliferation by regulating cell cycle-related proteins including p21, p27, CDK2, CDK4, Cyclin D1, and Cyclin E1. Furthermore, polydatin suppressed cell invasion and migration by regulating epithelial-mesenchymal transition (EMT) markers, including E-cadherin, N-cadherin, Snail and Slug. The c-Myc, as a proto-oncogene, is considered to be closely associated with the proliferation and metastasis of tumor cells. After polydatin treatment, the protein expression of c-Myc showed a significant decrease. Based on these data, we overexpressed c-Myc in cervical cancer cells and observed that the overexpression of c-Myc rescued the inhibitory effect of polydatin on cell proliferation and metastasis. These results indicated that polydatin can inhibit cell proliferation and metastasis through suppressing the c-Myc expression in human cervical cancer.
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http://dx.doi.org/10.3389/fcell.2021.587218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072354PMC
April 2021

Dehydrodiisoeugenol inhibits colorectal cancer growth by endoplasmic reticulum stress-induced autophagic pathways.

J Exp Clin Cancer Res 2021 Apr 10;40(1):125. Epub 2021 Apr 10.

State Key Laboratory of Silkworm Genome Biology, College of Sericulture, Textile and Biomass sciences, Southwest University, #2, Tiansheng Rd., Beibei District, Chongqing, 400716, China.

Background: Dehydrodiisoeugenol (DEH), a novel lignan component extracted from nutmeg, which is the seed of Myristica fragrans Houtt, displays noticeable anti-inflammatory and anti-allergic effects in digestive system diseases. However, the mechanism of its anticancer activity in gastrointestinal cancer remains to be investigated.

Methods: In this study, the anticancer effect of DEH on human colorectal cancer and its underlying mechanism were evaluated. Assays including MTT, EdU, Plate clone formation, Soft agar, Flow cytometry, Electron microscopy, Immunofluorescence and Western blotting were used in vitro. The CDX and PDX tumor xenograft models were used in vivo.

Results: Our findings indicated that treatment with DEH arrested the cell cycle of colorectal cancer cells at the G1/S phase, leading to significant inhibition in cell growth. Moreover, DEH induced strong cellular autophagy, which could be inhibited through autophagic inhibitors, with a rction in the DEH-induced inhibition of cell growth in colorectal cancer cells. Further analysis indicated that DEH also induced endoplasmic reticulum (ER) stress and subsequently stimulated autophagy through the activation of PERK/eIF2α and IRE1α/XBP-1 s/CHOP pathways. Knockdown of PERK or IRE1α significantly decreased DEH-induced autophagy and retrieved cell viability in cells treated with DEH. Furthermore, DEH also exhibited significant anticancer activities in the CDX- and PDX-models.

Conclusions: Collectively, our studies strongly suggest that DEH might be a potential anticancer agent against colorectal cancer by activating ER stress-induced inhibition of autophagy.
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http://dx.doi.org/10.1186/s13046-021-01915-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035743PMC
April 2021

Dihydrocapsaicin Inhibits Cell Proliferation and Metastasis in Melanoma Down-regulating β-Catenin Pathway.

Front Oncol 2021 23;11:648052. Epub 2021 Mar 23.

State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.

Dihydrocapsaicin (DHC) is one of the main components of capsaicinoids in Capsicum. It has been reported that DHC exerts anti-cancer effects on diverse malignant tumors, such as colorectal cancer, breast cancer, and glioma. However, studies focused on the effect of DHC upon melanoma have rarely been done. In the present study, melanoma A375 and MV3 cell lines were treated with DHC and the cell proliferation, migration, and invasion were significantly suppressed. Furthermore, DHC effectively inhibited xenograft tumor growth and pulmonary metastasis of melanoma cells in NOD/SCID mice model. It was identified that β-catenin, which plays significant roles in cell proliferation and epithelial-mesenchymal transition, was down-regulated after DHC treatment. In addition, cyclin D1, c-Myc, MMP2, and MMP7, which are critical in diverse cellular process regulation as downstream proteins of β-catenin, were all decreased. Mechanistically, DHC accelerates ubiquitination of β-catenin and up-regulates the beta-transducin repeat containing E3 ubiquitin protein ligase (BTRC) in melanoma cells. The DHC induced suppression of cell proliferation, migration, and invasion were partly rescued by exogenous β-catenin overexpression, both and . Taken together, DHC may serve as a candidate natural compound for human melanoma treatment through β-catenin pathway.
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http://dx.doi.org/10.3389/fonc.2021.648052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023049PMC
March 2021

Molecular Mechanisms of Dysregulation in Cancers.

Front Oncol 2020 3;10:625332. Epub 2021 Feb 3.

State Key Laboratory of Silkworm Genome Biology, College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing, China.

, a member of proto-oncogene family, encodes a basic helix-loop-helix transcription factor N-MYC. Abnormal expression of N-MYC is correlated with high-risk cancers and poor prognosis. Initially identified as an amplified oncogene in neuroblastoma in 1983, the oncogenic effect of N-MYC is expanded to multiple neuronal and nonneuronal tumors. Direct targeting N-MYC remains challenge due to its "undruggable" features. Therefore, alternative therapeutic approaches for targeting -driven tumors have been focused on the disruption of transcription, translation, protein stability as well as synthetic lethality of . In this review, we summarize the latest advances in understanding the molecular mechanisms of dysregulation in cancers.
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http://dx.doi.org/10.3389/fonc.2020.625332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886978PMC
February 2021

Immunodiagnosis and Immunotherapeutics Based on Human Papillomavirus for HPV-Induced Cancers.

Front Immunol 2020 8;11:586796. Epub 2021 Jan 8.

State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, College of Sericulture & Textile & Biomass Science, Southwest University, Chongqing, China.

Infection with human papillomavirus (HPV) is one of the main causes of malignant neoplasms, especially cervical, anogenital, and oropharyngeal cancers. Although we have developed preventive vaccines that can protect from HPV infection, there are still many new cases of HPV-related cancers worldwide. Early diagnosis and therapy are therefore important for the treatment of these diseases. As HPVs are the major contributors to these cancers, it is reasonable to develop reagents, kits, or devices to detect and eliminate HPVs for early diagnosis and therapeutics. Immunological methods are precise strategies that are promising for the accurate detection and blockade of HPVs. During the last decades, the mechanism of how HPVs induce neoplasms has been extensively elucidated, and several oncogenic HPV early proteins, including E5, E6, and E7, have been shown to be positively related to the oncogenesis and malignancy of HPV-induced cancers. These oncoproteins are promising biomarkers for diagnosis and as targets for the therapeutics of HPV-related cancers. Importantly, many specific monoclonal antibodies (mAbs), or newly designed antibody mimics, as well as new immunological kits, devices, and reagents have been developed for both the immunodiagnosis and immunotherapeutics of HPV-induced cancers. In the current review, we summarize the research progress in the immunodiagnosis and immunotherapeutics based on HPV for HPV-induced cancers. In particular, we depict the most promising serological methods for the detection of HPV infection and several therapeutical immunotherapeutics based on HPV, using immunological tools, including native mAbs, radio-labelled mAbs, affitoxins (affibody-linked toxins), intracellular single-chain antibodies (scFvs), nanobodies, therapeutical vaccines, and T-cell-based therapies. Our review aims to provide new clues for researchers to develop novel strategies and methods for the diagnosis and treatment of HPV-induced tumors.
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http://dx.doi.org/10.3389/fimmu.2020.586796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820759PMC
June 2021

CSN6 promotes melanoma proliferation and metastasis by controlling the UBR5-mediated ubiquitination and degradation of CDK9.

Cell Death Dis 2021 01 22;12(1):118. Epub 2021 Jan 22.

State Key Laboratory of Silkworm Genome Biology, Southwest University, 400715, Chongqing, China.

As a critical subunit of the constitutive photomorphogenesis 9 (COP9) signalosome (CSN), CSN6 is upregulated in some human cancers and plays critical roles in tumorigenesis and progression, but its biological functions and molecular mechanisms in melanoma remain unknown. Our study showed that CSN6 expression was upregulated in melanoma patients and cells, and correlated with poor survival in melanoma patients. In melanoma cells, CSN6 knockdown remarkably inhibited cell proliferation, tumorigenicity, migration, and invasion, whereas CSN6 recovery rescued the proliferative and metastatic abilities. Notably, we identified that CSN6 stabilized CDK9 expression by reducing CDK9 ubiquitination levels, thereby activating CDK9-mediated signaling pathways. In addition, our study described a novel CSN6-interacting E3 ligase UBR5, which was negatively regulated by CSN6 and could regulate the ubiquitination and degradation of CDK9 in melanoma cells. Furthermore, in CSN6-knockdown melanoma cells, UBR5 knockdown abrogated the effects caused by CSN6 silencing, suggesting that CSN6 activates the UBR5/CDK9 pathway to promote melanoma cell proliferation and metastasis. Thus, this study illustrates the mechanism by which the CSN6-UBR5-CDK9 axis promotes melanoma development, and demonstrate that CSN6 may be a potential biomarker and anticancer target in melanoma.
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http://dx.doi.org/10.1038/s41419-021-03398-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822921PMC
January 2021

Pathological and Prognostic Indications of the mdig Gene in Human Lung Cancer.

Cell Physiol Biochem 2021 Jan;55(S2):13-28

Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA,

Background/aims: The mineral-dust-induced gene mdig is a lung-cancer-associated oncogene. The focus of this study is to evaluate the expression status of mdig in lung cancer and to assess its influence in predicting the patient's overall survival.

Methods: Using high-density tissue microarrays and clinical samples of synchronous multiple primary lung cancer (SMPLC), we investigated the expression of mdig through immunohistochemistry and utilized the open-access lung cancer patient databases containing genomic and transcriptomic data from the UCSC Xena and TCGA web platforms to determine the prognostic values of mdig expression status among different subtypes of lung cancer.

Results: mdig is upregulated in smokers and in lung squamous cell carcinoma. High mdig expression predicted poor overall survival in lung squamous cell carcinoma and female smokers. Among tumor tissues from SMPLC patients, we not only unraveled the highest positive rate of mdig expression, but also revealed a unique cytoplasmic, rather than nuclear localization of mdig protein. Furthermore, by inspecting some pathological but not cancerous lung tissues, we believe that mdig is required for the transformation of non-cancerous lung cells to the fully-fledged cancer cells.

Conclusion: These data suggested that mdig is involved in various stages of lung carcinogenesis, possibly through the epigenetic regulation on some critical cancer-associated genes, and increased mdig expression is an important prognostic factor for some types of lung cancer.
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http://dx.doi.org/10.33594/000000322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140388PMC
January 2021

The Roles of Integrin α5β1 in Human Cancer.

Onco Targets Ther 2020 31;13:13329-13344. Epub 2020 Dec 31.

State Key Laboratory of Silkworm Genome Biology, Key Laboratory for Sericulture Biology and Genetic Breeding, Ministry of Agriculture and Rural Affairs, Southwest University, Chongqing 400716, People's Republic of China.

Cell adhesion to the extracellular matrix has important roles in tissue integrity and human health. Integrins are heterodimeric cell surface receptors that are composed by two non-covalently linked alpha and beta subunits that mainly participate in the interaction of cell-cell adhesion and cell-extracellular matrix and regulate cell motility, adhesion, differentiation, migration, proliferation, etc. In mammals, there have been eighteen α subunits and 8 β subunits and so far 24 distinct types of αβ integrin heterodimers have been identified in humans. Integrin α5β1, also known as the fibronectin receptor, is a heterodimer with α5 and β1 subunits and has emerged as an essential mediator in many human carcinomas. Integrin α5β1 alteration is closely linked to the progression of several types of human cancers, including cell proliferation, angiogenesis, tumor metastasis, and cancerogenesis. In this review, we will introduce the functions of integrin α5β1 in cancer progression and also explore its regulatory mechanisms. Additionally, the potential clinical applications as a target for cancer imaging and therapy are discussed. Collectively, the information reviewed here may increase the understanding of integrin α5β1 as a potential therapeutic target for cancer.
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http://dx.doi.org/10.2147/OTT.S273803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781020PMC
December 2020

Tubeimoside I Inhibits Cell Proliferation and Induces a Partly Disrupted and Cytoprotective Autophagy Through Rapidly Hyperactivation of MEK1/2-ERK1/2 Cascade via Promoting PTP1B in Melanoma.

Front Cell Dev Biol 2020 17;8:607757. Epub 2020 Dec 17.

State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, College of Sericulture and Textile and Biomass, Chongqing, China.

Tubeimoside I (TBMS1), also referred to as tubeimoside A, is a natural compound extracted from the plant Tu Bei Mu (), which is a traditional Chinese herb used to treat multiple diseases for more than 1,000 years. Studies in recent years reported its anti-tumor activity in several cancers. However, whether it is effective in melanoma remains unknown. In the current study, we discovered that TBMS1 treatment inhibited melanoma cell proliferation and tumorigenecity . Besides, we also observed that TBMS1 treatment induced a partly disrupted autophagy, which still remained a protective role, disruption of which by chloroquine (CQ) or 3-methyladenine (3-MA) enhanced TBMS1-induced cell proliferation inhibition. CQ combined with TBMS1 even induced cellular apoptosis. BRAF(V600E) mutation and its continuously activated downstream MEK1/2-ERK1/2 cascade are found in 50% of melanomas and are important for malanomagenesis. However, hyperactivating MEK1/2-ERK1/2 cascade can also inhibit tumor growth. Intriguingly, we observed that TBMS1 rapidly hyperactivated MEK1/2-ERK1/2, inhibition of which by its inhibitor SL-327 rescued the anti-cancerous effects of TBMS1. Besides, the targets of TBMS1 were predicted by the ZINC Database based on its structure. It is revealed that protein-tyrosine phosphatase 1B (PTP1B) might be one of the targets of TBMS1. Inhibition of PTP1B by its selective inhibitor TCS401 or shRNA rescued the anti-cancerous effects of TBMS1 in melanoma cells. These results indicated that TBMS1 might activate PTP1B, which further hyperactivates MEK1/2-ERK1/2 cascade, thereby inhibiting cell proliferation in melanoma. Our results provided the potentiality of TBMS1 as a drug candidate for melanoma therapy and confirmed that rapidly hyperactivating an oncogenic signaling pathway may also be a promising strategy for cancer treatment.
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http://dx.doi.org/10.3389/fcell.2020.607757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773826PMC
December 2020

Facile engineering of silk fibroin capped AuPt bimetallic nanozyme responsive to tumor microenvironmental factors for enhanced nanocatalytic therapy.

Theranostics 2021 1;11(1):107-116. Epub 2021 Jan 1.

State Key Laboratory of Silkworm Genome Biology, School of Materials and Energy, Southwest University, Chongqing 400715, China.

Reactive oxygen species (ROS), as a category of highly reactive molecules, are attractive for eliminating tumor cells . However, the intrinsic tumor microenvironment (TME) always compromises treatment efficacy. In another aspect, silk fibroin (SF), as a category of natural biomacromolecules, is highly promising for synthesis of metallic nanocrystals via biomineralization. As a proof-of-concept study, AuPt bimetallic nanozyme derived from bioinspired crystallization of chloroauric acid and chloroplatinic acid was facilely developed in the presence of silk fibroin (SF). Antitumor effects caused by the as-synthesized [email protected] (APS) nanozyme were demonstrated in 4T1 tumor cells and xenograft tumor models . APS nanozyme can decompose glucose to constantly supply HO and deplete intracellular glutathione (GSH). APS nanozyme can simultaneously convert adsorbed O and endogenic HO into superoxide radicals (O) and hydroxyl radical (OH), respectively, upon highly efficient catalytic reaction. Subsequently, these cytotoxic ROS cause irreversible damage to the cell membrane, nucleic acid and mitochondria of tumors. Upon fluorescence/photoacoustic (FL/PA)-imaging guidance, remarkable tumor damage based on the current nanoplatform was confirmed . The objective of our investigation is to supply more useful insights on the development of SF-based nanocatalysts, which are specifically responsive to TME for extremely efficient tumor theranostics.
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http://dx.doi.org/10.7150/thno.50486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681078PMC
January 2021

Bruceine D inhibits Cell Proliferation Through Downregulating LINC01667/MicroRNA-138-5p/Cyclin E1 Axis in Gastric Cancer.

Front Pharmacol 2020 24;11:584960. Epub 2020 Nov 24.

State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, College of Sericulture and Textile and Biomass Science, Southwest University, Chongqing, China.

Gastric cancer is one of the most common malignant tumors. Bruceine D (BD) is one of the extracts of . In recent years, it has been reported that BD has anti-tumor activity in some human cancers through different mechanisms. Here, this study try to explore the effect of BD on gastric cancer and its regulatory mechanism. Cell proliferation ability was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assays, 5-bromo-2-deoxyuridine (BrdU) staining and soft agar colony formation assay, respectively. The tumor xenograft model was used to verify the effect of BD on the tumorigenicity of gastric cancer cells . Flow cytometry analysis and Western blot assay were performed to detect cell cycle and apoptosis. Gastric cancer cells were analyzed by transcriptome sequencing. The interaction between LINC01667, microRNA-138-5p (miR-138-5p) and Cyclin E1 was verified by dual luciferase experiment and RT-PCR assays. We found that BD significantly inhibited cell proliferation and induced cell cycle arrest at S phase in gastric cancer cells. Transcriptome analysis found that the expression of a long non-coding RNA, LINC01667, were significantly down-regulated after BD treatment. Mechanically, it was discovered that LINC01667 upregulated the expression of Cyclin E1 by sponging miR-138-5p. Furthermore, BD enhanced the chemosensitivity of gastric cancer cells to doxorubicin, a clinically used anti-cancer agent. BD inhibit the growth of gastric cancer cells by downregulating the LINC01667/miR-138-5p/Cyclin E1 axis. In addition, BD enhances the chemosensitivity of gastric cancer cells to doxorubicin. This study indicates that BD may be used as a candidate drug for the treatment of patients with gastric cancer.
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http://dx.doi.org/10.3389/fphar.2020.584960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774499PMC
November 2020

A hemocyte-specific cathepsin L-like cysteine protease is involved in response to 20-hydroxyecdysone and microbial pathogens stimulation in silkworm, Bombyx mori.

Mol Immunol 2021 03 26;131:78-88. Epub 2020 Dec 26.

State Key Laboratory of Silkworm Genome Biology, Key Laboratory for Sericulture Biology and Genetic Breeding, Ministry of Agriculture and Rural Affairs, College of Biotechnology, Southwest University, Chongqing 400716, China; Cancer Center, Medical Research Institute, Southwest University, Chongqing 400716, China; Chongqing Engineering and Technology Research Centre for Silk Biomaterials and Regenerative Medicine, Chongqing 400716, China; Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Chongqing 400716, China. Electronic address:

Cathepsin L protease belongs to the papain-like cysteine proteases family, plays indispensable roles in animals' pathological and physiological processes. However, little is known about Cathepsin L in silkworm, Bombyx mori. Herein, a novel Cathepsin L-like (Cat L-like) was cloned and identified from silkworm by the rapid amplification of cDNA ends (RACE). Cat L-like contains an intact open reading frame (ORF) of 1 668 bp and encodes 556 amino acid residues, consisting of a signal peptide, typical cathepsins' inhibitor_I29, and pept_C1 domain. Cat L-like is specifically and highly expressed in hemocytes. The cathepsin (including Cathepsin L, B, and H) crude extract from hemocytes had typical substrate specific catalytic activities and were sensitive to pH and temperature. Cat L-like up-regulated considerably after 20-hydroxyecdysone (20-E) administration, indicating that Cat L-like may be regulated by insect hormone. The responses of Cat L-like against bacterial infection suggest it may play essential roles in silkworm immunity. Overall, our studies provide a theoretical basis and insights to further investigate the functions of Cat L-like and in insects' innate immunity mechanisms.
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http://dx.doi.org/10.1016/j.molimm.2020.12.013DOI Listing
March 2021

Deficiency of G9a Inhibits Cell Proliferation and Activates Autophagy via Transcriptionally Regulating c-Myc Expression in Glioblastoma.

Front Cell Dev Biol 2020 27;8:593964. Epub 2020 Nov 27.

State Key Laboratory of Silkworm Genome Biology, College of Sericulture, Textile and Biomass Sciences, Southwest University, Chongqing, China.

Glioblastoma is an aggressive and difficult to treat cancer. Recent data have emerged implicating that histone modification level may play a crucial role in glioma genesis. The histone lysine methyltransferase G9a is mainly responsible for the mono- and di-methylation of histone H3 lysine 9 (H3K9), whose overexpression is associated with a more aggressive phenotype in cancer. However, the detailed correlations between G9a and glioblastoma genesis remain to be further elucidated. Here, we show that G9a is essential for glioblastoma carcinogenesis and reveal a probable mechanism of it in cell proliferation control. We found that G9a was highly expressed in glioblastoma cells, and knockdown or inhibition of G9a significantly repressed cell proliferation and tumorigenesis ability both and . Besides, knockdown or inhibition of G9a led to a cell cycle arrest in G2 phase, as well as decreased the expression of CDK1, CDK2, Cyclin A2, and Cyclin B1, while it induced the activation of autophagy. Further investigation showed that G9a deficiency induced cell proliferation suppression, and activation of autophagy was rescued by overexpression of the full-length c-Myc. Chromatin immunoprecipitation (ChIP) assay showed that G9a was enriched on the -2267 to -1949 region of the c-Myc promoter in LN-229 cells and the -1949 to -1630 region of the c-Myc promoter in U-87 MG cells. Dual-luciferase reporter assay showed that c-Myc promoter activity was significantly reduced after knockdown or inhibition of G9a. Our study shows that G9a controls glioblastoma cell proliferation by transcriptionally modulating oncogene c-Myc and provides insight into the capabilities of G9a working as a potential therapeutic target in glioblastoma.
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http://dx.doi.org/10.3389/fcell.2020.593964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729084PMC
November 2020

Scavenger receptor B8 improves survivability by mediating innate immunity in silkworm, Bombyx mori.

Dev Comp Immunol 2021 Mar 5;116:103917. Epub 2020 Nov 5.

State Key Laboratory of Silkworm Genome Biology, Key Laboratory of Sericultural Biology and Genetic Breeding, Ministry of Agriculture, Southwest University, China; Cancer Center, Medical Research Institute, Southwest University, Chongqing, 400716, China; Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, 400716, Chongqing, China; Southwest University Engineering Research Center for Cancer Biomedical and Translational Medicine, 400715, Chongqing, China. Electronic address:

Scavenger receptor class B (SR-B) is an extracellular transmembrane glycoprotein that plays a vital role in innate immunity. Although SR-Bs have been widely studied in vertebrates, their functions remained to elucidate in insects. Here, we identified and characterized a scavenger receptor class B member from the silkworm, Bombyx mori (designated as BmSCRB8). BmSCRB8 is broadly expressed in various immune tissues/organs, including fat body, gut, and hemocyte. Its expression is dramatically enhanced after challenge with different types of bacteria or pathogen-associated molecular patterns (PAMPs). The recombinant BmSCRB8 protein can detect different types of bacteria by directly binding to PAMPs and significantly improve the bacterial clearance in vivo. After knockdown of BmSCRB8, the pathogenic bacterial clearance was strongly impaired, and several AMP genes were down-regulated following E. coli challenge. Moreover, pathogenic bacteria's treatment following the depletion of BmSCRB8 remarkably decreased silkworm larvae's survival rate. Taken together, these results demonstrate that BmSCRB8 acts as a pattern recognition protein and plays an essential role in silkworm innate immunity by enhancing bacterial clearance and contributing to the production of AMPs in vivo.
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http://dx.doi.org/10.1016/j.dci.2020.103917DOI Listing
March 2021

Lycorine hydrochloride inhibits cell proliferation and induces apoptosis through promoting FBXW7-MCL1 axis in gastric cancer.

J Exp Clin Cancer Res 2020 Oct 30;39(1):230. Epub 2020 Oct 30.

State Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, #1, Tiansheng Rd., Beibei District, Chongqing, 400716, China.

Background: Lycorine hydrochloride (LH), an alkaloid extracted from the bulb of the Lycoris radiata, is considered to have anti-viral, anti-malarial, and anti-tumorous effects. At present, the underlying mechanisms of LH in gastric cancer remain unclear. MCL1, an anti-apoptotic protein of BCL2 family, is closely related to drug resistance of tumor. Therefore, MCL1 is considered as a potential target for cancer treatment.

Methods: The effect of LH on gastric cancer was assessed in vitro (by MTT, BrdU, western blotting…) and in vivo (by immunohistochemistry).

Results: In this study, we showed that LH has an anti-tumorous effect by down-regulating MCL1 in gastric cancer. Besides, we unveiled that LH reduced the protein stability of MCL1 by up-regulating ubiquitin E3 ligase FBXW7, arrested cell cycle at S phase and triggered apoptosis of gastric cancer cells. Meanwhile, we also demonstrated that LH could induce apoptosis of the BCL2-drug-resistant-cell-lines. Moreover, PDX (Patient-Derived tumor xenograft) model experiment proved that LH combined with HA14-1 (inhibitor of BCL2), had a more significant therapeutic effect on gastric cancer.

Conclusions: The efficacy showed in our data suggests that lycorine hydrochloride is a promising anti-tumor compound for gastric cancer.
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http://dx.doi.org/10.1186/s13046-020-01743-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602321PMC
October 2020

NUCKS promotes cell proliferation and suppresses autophagy through the mTOR-Beclin1 pathway in gastric cancer.

J Exp Clin Cancer Res 2020 Sep 21;39(1):194. Epub 2020 Sep 21.

State Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, No.2 Tiansheng Road, Beibei District, Chongqing, 400716, China.

Background: Nuclear casein kinase and cyclin-dependent kinase substrate (NUCKS), a novel gene first reported in 2001, is a member of the high mobility group (HMG) family. Although very little is known regarding the biological roles of NUCKS, emerging clinical evidence suggests that the NUCKS protein can be used as a biomarker and therapeutic target in various human ailments, including several types of cancer.

Methods: We first assessed the potential correlation between NUCKS expression and gastric cancer prognosis. Then functional experiments were conducted to evaluate the effects of NUCKS in cell proliferation, cell cycle, apoptosis and autophagy. Finally, the roles of NUCKS on gastric cancer were examined in vivo.

Results: We found that NUCKS was overexpressed in gastric cancer patients with poor prognosis. Through manipulating NUCKS expression, it was observed to be positively associated with cell proliferation in vitro and in vivo. NUCKS knockdown could induce cell cycle arrest and apoptosis. Then further investigation indicated that NUCKS knockdown could also significantly induce a marked increase in autophagy though the mTOR-Beclin1 pathway, which could be was rescued by NUCKS restoration. Moreover, silencing Beclin1 in NUCKS knockdown cells or adding rapamycin in NUCKS-overexpressed cells also confirmed these results.

Conclusions: Our findings revealed that NUCKS functions as an oncogene and an inhibitor of autophagy in gastric cancer. Thus, the downregulation or inhibition of NUCKS may be a potential therapeutic strategy for gastric cancer.
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http://dx.doi.org/10.1186/s13046-020-01696-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504682PMC
September 2020

Bmintegrin β1: A broadly expressed molecule modulates the innate immune response of Bombyx mori.

Dev Comp Immunol 2021 Jan 18;114:103869. Epub 2020 Sep 18.

State Key Laboratory of Silkworm Genome Biology, Key Laboratory for Sericulture Biology and Genetic Breeding, Ministry of Agriculture and Rural Affairs, College of Biotechnology, Southwest University, Chongqing, 400716, China; Cancer Center, Medical Research Institute, Southwest University, Chongqing, 400716, China; Chongqing Engineering and Technology Research Centre for Silk Biomaterials and Regenerative Medicine, Chongqing, 400716, China; Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Chongqing, 400716, China. Electronic address:

Integrins are transmembrane glycoproteins that are broadly distributed in living organisms. As a heterodimer, they contain an α and a β subunit, which are reported to be associated with various physiological and pathological processes. In the present study, a 2502 bp full-length cDNA sequence of Bmintegrin β1 was obtained from the silkworm, Bombyx mori. Bmintegrin β1 belongs to the β subunit of the integrin family and contains several typical structures of integrins. Gene expression profile analysis demonstrated that Bmintegrin β1 was ubiquitously expressed in all tested tissues and organs, with the maximum expression levels in fat body and hemocytes. The immunofluorescence results showed that Bmintegrin β1 was located in the cell membrane and widely distributed in fat bodies and different types of hemocytes. Bmintegrin β1 expression was remarkably increased after challenging with different kinds of bacteria and pathogen-associated molecular patterns (PAMPs). Further investigation revealed that Bmintegrin β1 could participate in the agglutination of pathogenic bacteria possibly through direct binding with the relative bacteria and PAMPs. Altogether, this study provides a novel insight into the immune functional features of Bmintegrin β1.
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http://dx.doi.org/10.1016/j.dci.2020.103869DOI Listing
January 2021

CCDC25: precise navigator for neutrophil extracellular traps on the prometastatic road.

Signal Transduct Target Ther 2020 08 24;5(1):162. Epub 2020 Aug 24.

State Key Laboratory of Silkworm Genome Biology, College of Biotechnology, Southwest University, Chongqing, China.

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http://dx.doi.org/10.1038/s41392-020-00285-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445241PMC
August 2020

E2F7-EZH2 axis regulates PTEN/AKT/mTOR signalling and glioblastoma progression.

Br J Cancer 2020 10 20;123(9):1445-1455. Epub 2020 Aug 20.

State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.

Background: E2F transcription factors are considered to be important drivers of tumour growth. E2F7 is an atypical E2F factor, and its role in glioblastoma remains undefined.

Methods: E2F7 expression was examined in patients by IHC and qRT-PCR. The overall survival probability was determined by statistical analyses. MTT assay, colony formation, cell-cycle assay, cell metastasis and the in vivo model were employed to determine the functional role of E2F7 in glioblastoma. Chromatin immunoprecipitation, luciferase assay and western blot were used to explore the underlying mechanisms.

Results: E2F7 was found to be up-regulated in glioblastoma patients, and high E2F7 expression was associated with poor overall survival in glioblastoma patients. Functional studies showed that E2F7 promoted cell proliferation, cell-cycle progression, cell metastasis and tumorigenicity abilities in vitro and in vivo. E2F7 promoted the transcription of EZH2 by binding to its promoter and increased H3K27me3 level. EZH2 recruited H3K27me3 to the promoter of PTEN and inhibited PTEN expression, and then activated the AKT/mTOR signalling pathway. In addition, restored expression of EZH2 recovered the abilities of cell proliferation and metastasis in E2F7-silencing cells.

Conclusion: Collectively, our findings indicate that E2F7 promotes cell proliferation, cell metastasis and tumorigenesis via EZH2-mediated PTEN/AKT/mTOR pathway in glioblastoma.
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http://dx.doi.org/10.1038/s41416-020-01032-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591888PMC
October 2020

Biomimetic [email protected] nanozyme responsive to multiple tumor microenvironmental clues for augmenting chemodynamic therapy.

Biomaterials 2020 10 3;257:120279. Epub 2020 Aug 3.

State Key Laboratory of Silkworm Genome Biology, School of Materials and Energy, Southwest University, Chongqing, 400715, China; Chongqing Engineering Research Center for Micro-Nano Biomedical Materials and Devices, Southwest University, Chongqing, 400715, China. Electronic address:

Chemodynamic therapy (CDT), an emerging therapeutic strategy, has been recently exploited for in situ treatment through Fenton or Fenton-like reactions to generate cytotoxic reactive oxygen species (ROS). However, current systems rely significantly on the high local oxygen levels and strongly acidic conditions (pH = 3.0-5.0). Simultaneously, the produced ROS can be rapidly consumed by intracellular glutathione (GSH) in the electron transport chain. Herein, an original and biomimetic [email protected] nanocatalyst was prepared based on the assembly of Au and Pt nanoparticles (NPs) on the surface of hollow CoO nanocapsules. The as-synthesized nanozyme exhibits extremely high stability under physiological conditions, whereas it undergoes spontaneous disintegration in the unique tumor microenvironment (TME). Subsequently, the decomposition products can catalyze a cascade of biochemical reactions to produce abundant ROS without any external stimuli. Thus, the present nanoplatform can increase intracellular ROS levels through continuous supply of HO, relief of local hypoxia and depletion of GSH, which result in remarkable and specific tumor damage both in vitro and in vivo. The findings of this study highlight the promising potential of [email protected] nanocatalyst as a TME-responsive CDT nanomagnet for highly efficient tumor therapy.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120279DOI Listing
October 2020

PHF14 Promotes Cell Proliferation and Migration through the AKT and ERK1/2 Pathways in Gastric Cancer Cells.

Biomed Res Int 2020 10;2020:6507510. Epub 2020 Jun 10.

State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.

PHF14 is a new member belonging to PHD finger proteins. PHF14 is involved in multiple biologic processes including Dandy-Walker syndrome, mesenchyme growth, lung fibrosis, renal fibrosis, persistent pulmonary hypertension, and tumor development. This study aims to explore whether PHF14 plays an important role in gastric cancer. Here, PHF14 is indicated as a tumor promoter. The expression of PHF14 enhances no matter in clinical samples or in gastric cancer cells. High expression of PHF14 impairs survival of patients. Attenuation of PHF14 inhibits cell proliferation in gastric cancer cells. PHF14 downregulation inhibits the expression of cell cycle-related proteins, CDK6 and cyclin D1. Furthermore, silencing of PHF14 reduces the level of phosphorylated AKT as well as phosphorylated ERK1/2. Finally, downregulation of PHF14 in gastric cancer cells inhibits colony formation and tumorigenesis These results indicate that PHF14 promotes tumor development in gastric cancer, so PHF14 thereby acts as a potential target for gastric cancer therapy.
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http://dx.doi.org/10.1155/2020/6507510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305535PMC
March 2021

Histone Deacetylase Inhibitor Trichostatin A Suppresses Cell Proliferation and Induces Apoptosis by Regulating the PI3K/AKT Signalling Pathway in Gastric Cancer Cells.

Anticancer Agents Med Chem 2020 ;20(17):2114-2124

School of Life Sciences, Southwest University, Chongqing, 400715, China

Background: Gastric cancer, a common malignant tumour worldwide, has a relatively poor prognosis and is a serious threat to human health. Histone Deacetylase Inhibitors (HDACi) are anticancer agents that are known to affect the cell growth of different cancer types. Trichostatin A (TSA) selectively inhibits the class I and II mammalian Histone Deacetylase (HDAC) family enzymes and regulates many cell processes. Still, the underlying mechanisms of HDACs are not fully understood in gastric cancer.

Objective: This study aims to investigate the antitumor effect and the mechanism of growth modulation of gastric cancer cells by TSA.

Methods: The cell proliferation of gastric cancer cells was measured by MTT and BrdU immunofluorescence assays. Soft agar assay was used to detect the colony formation ability of gastric cancer cells. Flow cytometry was used to examine cell cycle and apoptosis. Western blot was employed to detect protein expression of target factors.

Results: TSA inhibits the proliferation of MKN-45 and SGC-7901 cells and leads to significant repression of colony number and size. Flow cytometry assays show TSA induces cell cycle arrest at G1 phase and apoptosis, and TSA effects the expression of related factors in the mitochondrial apoptotic signalling and cell cycle-related regulatory pathways. Furthermore, TSA increased histone H3K27 acetylation and downregulated the expression of PI3K and p-AKT.

Conclusion: Downregulating PI3K/AKT pathway activation is involved in TSA-mediated proliferation inhibition of gastric cancer.
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http://dx.doi.org/10.2174/1871520620666200627204857DOI Listing
June 2021

NUSAP1 potentiates chemoresistance in glioblastoma through its SAP domain to stabilize ATR.

Signal Transduct Target Ther 2020 04 22;5(1):44. Epub 2020 Apr 22.

State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.

NUSAP1, which is a microtubule-associated protein involved in mitosis, plays essential roles in diverse biological processes, especially in cancer biology. In this study, NUSAP1 was found to be overexpressed in GBM tissues in a grade-dependent manner compared with normal brain tissues. NUSAP1 was also highly expressed in GBM patients, dead patients, and GBM cells. In addition, NUSAP1 was found to participate in cell proliferation, apoptosis, and DNA damage in GBM cells. Ataxia telangiectasia and Rad3-related protein (ATR) are a primary sensor of DNA damage, and ATR is also a promising target in cancer therapy. Here, we found that NUSAP1 positively regulated the expression of ATR. Mechanistically, NUSAP1 suppressed the ubiquitin-dependent proteolysis of ATR. The SAP (SAF-A/B, Acinus, and PIAS) domain is a common motif of many SUMO (small ubiquitin-like modifier) E3 ligases, and this domain is involved in substrate recognition and ligase activity. This study further demonstrated that the SAP domain of NUSAP1 promoted the sumoylation of ATR, and thereby antagonized the ubiquitination of ATR. These results suggest that NUSAP1 stabilizes ATR by sumoylation. Moreover, NUSAP1 potentiated chemotherapeutic resistance to temozolomide (TMZ) and doxorubicin (DOX) through its SAP domain. Overall, this study indicates that NUSAP1 is a promising therapeutic target in GBM.
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http://dx.doi.org/10.1038/s41392-020-0137-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174393PMC
April 2020

Targeting cancer stem cell pathways for cancer therapy.

Signal Transduct Target Ther 2020 02 7;5(1). Epub 2020 Feb 7.

State Key Laboratory of Silkworm Genome Biology, Southwest University, 400716, Chongqing, China.

Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.
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http://dx.doi.org/10.1038/s41392-020-0110-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005297PMC
February 2020

The Emerging Roles of RNA Modifications in Glioblastoma.

Cancers (Basel) 2020 Mar 20;12(3). Epub 2020 Mar 20.

State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, College of Biotechnology, Southwest University, Beibei, Chongqing 400716, China.

Glioblastoma (GBM) is a grade IV glioma that is the most malignant brain tumor type. Currently, there are no effective and sufficient therapeutic strategies for its treatment because its pathological mechanism is not fully characterized. With the fast development of the Next Generation Sequencing (NGS) technology, more than 170 kinds of covalent ribonucleic acid (RNA) modifications are found to be extensively present in almost all living organisms and all kinds of RNAs, including ribosomal RNAs (rRNAs), transfer RNAs (tRNAs) and messenger RNAs (mRNAs). RNA modifications are also emerging as important modulators in the regulation of biological processes and pathological progression, and study of the epi-transcriptome has been a new area for researchers to explore their connections with the initiation and progression of cancers. Recently, RNA modifications, especially mA, and their RNA-modifying proteins (RMPs) such as methyltransferase like 3 (METTL3) and α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5), have also emerged as important epigenetic mechanisms for the aggressiveness and malignancy of GBM, especially the pluripotency of glioma stem-like cells (GSCs). Although the current study is just the tip of an iceberg, these new evidences will provide new insights for possible GBM treatments. In this review, we summarize the recent studies about RNA modifications, such as N-methyladenosine (mA), N,2'O-dimethyladenosine (mA), 5-methylcytosine (mC), N-methyladenosine (mA), inosine (I) and pseudouridine (ψ) as well as the corresponding RMPs including the writers, erasers and readers that participate in the tumorigenesis and development of GBM, so as to provide some clues for GBM treatment.
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http://dx.doi.org/10.3390/cancers12030736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140112PMC
March 2020