Publications by authors named "Guohong Hu"

70 Publications

Occludin is a target of Src kinase and promotes lipid secretion by binding to BTN1a1 and XOR.

PLoS Biol 2022 Jan 18;20(1):e3001518. Epub 2022 Jan 18.

School of Life Science and Technology, ShanghaiTech University, Shanghai, China.

Lipid droplets (LDs) have increasingly been recognized as an essential organelle for eukaryotes. Although the biochemistry of lipid synthesis and degradation is well characterized, the regulation of LD dynamics, including its formation, maintenance, and secretion, is poorly understood. Here, we report that mice lacking Occludin (Ocln) show defective lipid metabolism. We show that LDs were larger than normal along its biogenesis and secretion pathway in Ocln null mammary cells. This defect in LD size control did not result from abnormal lipid synthesis or degradation; rather, it was because of secretion failure during the lactation stage. We found that OCLN was located on the LD membrane and was bound to essential regulators of lipid secretion, including BTN1a1 and XOR, in a C-terminus-dependent manner. Finally, OCLN was a phosphorylation target of Src kinase, whose loss causes lactation failure. Together, we demonstrate that Ocln is a downstream target of Src kinase and promotes LD secretion by binding to BTN1a1 and XOR.
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http://dx.doi.org/10.1371/journal.pbio.3001518DOI Listing
January 2022

LncRNA HITT inhibits metastasis by attenuating Rab5-mediated endocytosis in lung adenocarcinoma.

Mol Ther 2022 Jan 8. Epub 2022 Jan 8.

School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang Province, China, 150001; Shenzhen Graduate School of Harbin Institute of Technology, Shenzhen, China, 518055. Electronic address:

Endocytosis of cell surface receptors is essential for cell migration and cancer metastasis. Rab5, a small GTPases of Rab family, is a key regulator of endosome dynamics and thus cell migration, however, how its activity is regulated yet remains to be addressed. Here, we identified a Rab5 inhibitor, a long non-coding RNA namely HITT (HIF-1α inhibitor at translation level). Our data show that HITT expression is inversely associated with advanced stages and poorly prognosis of lung adenocarcinoma patients with area under receiver operating characteristics (ROC) curve (AUC) 0.6473. Further study reveals that both endogenous and exogenous HITT inhibits single cell migration by repressing β1 integrin endocytosis in lung adenocarcinoma. Mechanistically, HITT is physically associated with Rab5 at switch I via 1248-1347nt and suppresses β1 integrin endocytosis and subsequent cancer metastasis by interfering with guanine nucleotide exchange factors (GEFs) for Rab5 binding. Collectively, these findings suggest that HITT directly participates in the regulation of Rab5 activity, leading to a decreased integrin internalization and cancer metastasis, which provides important insights into a mechanistic understanding of endocytosis and cancer metastasis.
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http://dx.doi.org/10.1016/j.ymthe.2022.01.014DOI Listing
January 2022

TGF-β1 induces epithelial-to-mesenchymal transition in chronic rhinosinusitis with nasal polyps through microRNA-182.

Asian Pac J Allergy Immunol 2021 Dec 26. Epub 2021 Dec 26.

The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences, Shanghai, China.

Background: Epithelial-to-mesenchymal transition (EMT) in nasal epithelial cells is involved in tissue remodeling of chronic rhinosinusitis with nasal polyps (CRSwNP). Our study investigated the molecular mechanisms that microRNA-182 (miR-182) regulated EMT in eosinophilic (Eos) and non-eosinophilic (non-Eos) CRSwNP.

Objective: To investigate the mechanism by which miR-182 regulates EMT in human nasal epithelial cells (hNEPCs).

Methods: The expression of EMT markers (E-cadherin, N-cadherin and vimentin), transforming growth factor (TGF)-β1, and miR-182 were determined by western blotting and reverse transcription-quantitative PCR (RT-qPCR). Fluorescence in situ hybridization (FISH) was used to detect the miR-182 localization. Additionally, EMT markers expression and cell morphology changes were checked upon treatment with TGF-β1, or TGF-β1 with miR-182 inhibitor, or miR-182 mimics, or miR-182 inhibitor alone in hNEPCs.

Results: In both Eos CRSwNP and non-Eos CRSwNP, the expression levels of E-cadherin were downregulated while the expression levels of N-cadherin, vimentin, TGF-β1 and miR-182 were significantly upregulated compared with control nasal tissues. Additionally, more significant changes in these EMT markers were observed in the Eos-CRSwNP when compared with the non-Eos CRSwNP. Invitro hNEPCs model, TGF-β1 upregulated miR-182 expression and promoted EMT in hNEPCs, indicated by changes in cell morphology and EMT markers expression. Furthermore, these upregulations were reversed by miR-182 inhibitor.

Conclusions: This study showed that miR-182-induced EMT in response to TGF-β1 might promote nasal polypogenesis in both Eos CRSwNP and non-Eos CRSwNP, thus providing potential targets for the future development of novel therapeutic approaches for the management of CRSwNP.
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http://dx.doi.org/10.12932/AP-040921-1224DOI Listing
December 2021

RSPO2 and RANKL signal through LGR4 to regulate osteoclastic premetastatic niche formation and bone metastasis.

J Clin Invest 2022 Jan;132(2)

Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.

Therapeutics targeting osteoclasts are commonly used treatments for bone metastasis; however, whether and how osteoclasts regulate premetastatic niche and bone tropism are largely unknown. In this study, we report that osteoclast precursors (OPs) can function as a premetastatic niche component that facilitates breast cancer (BCa) bone metastasis at early stages. At the molecular level, unbiased GPCR ligand/agonist screening in BCa cells suggested that R-spondin 2 (RSPO2) and RANKL, through interaction with their receptor LGR4, promoted osteoclastic premetastatic niche formation and enhanced BCa bone metastasis. This was achieved by RSPO2/RANKL-LGR4 signal modulating the WNT inhibitor DKK1 through Gαq and β-catenin signaling. DKK1 directly facilitated OP recruitment through suppression of its receptor LDL receptor-related protein 5 (LRP5) but not LRP6, upregulating Rnasek expression via inhibition of canonical WNT signaling. In clinical samples, RSPO2, LGR4, and DKK1 expression showed a positive correlation with BCa bone metastasis. Furthermore, soluble LGR4 extracellular domain (ECD) protein, acting as a decoy receptor for RSPO2 and RANKL, significantly alleviated bone metastasis and osteolytic lesions in a mouse bone metastasis model. These findings provide unique insights into the functional role of OPs as key components of the premetastatic niche for BCa bone metastasis and identify RSPO2/RANKL-LGR4 signaling as a promising target for inhibiting BCa bone metastasis.
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http://dx.doi.org/10.1172/JCI144579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8759794PMC
January 2022

Serum and glucocorticoid-regulated kinase 1 regulates transforming growth factor β1-connective tissue growth factor pathway in chronic rhinosinusitis.

Clin Immunol 2022 Jan 24;234:108895. Epub 2021 Nov 24.

Department of Otolaryngology-Head and Neck Surgery, Eye and ENT Hospital, Fudan University, No. 83, Fenyang Road, Xuhui District, Shanghai, China. Electronic address:

Purpose: Serum/glucocorticoid-regulated kinase 1 (SGK1) has been identified as a crucial regulator in fibrotic disorders. Herein, we explored SGK1 role in tissue remodeling of chronic rhinosinusitis (CRS).

Methods: Lentivirus was employed to generate an SGK1-overexpressing human bronchial epithelial cell (16HBE) line. To screen SGK1 downstream genes, RNA sequencing was performed on SGK1-overexpressing and control cell lines. To determine protein and gene expression levels, immunohistochemistry, western blotting, and quantitative real-time polymerase chain reaction were employed. Correlation analysis was performed using mRNA expression levels of SGK1, transforming growth factor β1 (TGF-β1), and connective tissue growth factor (CTGF) derived from CRS mucosal tissue and GEO database. Gene set enrichment analysis was conducted using gene sets from Molecular Signatures Database. The severity of symptoms in CRS patients was assessed using the 22-Item Sinonasal Outcome Test.

Results: SGK1 overexpression significantly increased the expression of connective tissue growth factor (CTGF) in 16HBE cells (P < 0.01). Consistently, CTGF protein level was considerably greater in mucosal tissue of CRS without nasal polyps (CRSsNP) than in CRS with nasal polyps (CRSwNP) (P < 0.05) or in control subjects (P < 0.01). TGF-β1 protein level was higher in mucosal tissue of CRSsNP patients than in CRSwNP patients (P < 0.001) or in the control group (P < 0.01). mRNA levels of SGK1 and CTGF (P < 0.05, r = 0.668; P = 0.001, r = 0.630), TGF-β1 and CTGF (P < 0.05, r = 0.560; P < 0.05, r = 0.420), as well as SGK1 and TGF-β1(P < 0.05, r = 0.612; P < 0.05, r = 0.524) were significantly correlated in CRS mucosal tissue and GSE36830 dataset, respectively. TGF-β1-induced upregulated genes were significantly enriched in SGK1 overexpression group. In vitro assays, TGF-β1 promoted SGK1 and CTGF expression in a concentration- and time-dependent manner. Administrating an SGK1 inhibitor, GSK650394, significantly inhibited TGF-β1-induced CTGF expression in 16HBE and dispersed primary nasal polyp cells.

Conclusions: TGF-β1 stimulation significantly increases SGK1 and CTGF expression. By regulating TGF-β1-CTGF pathway, SGK1 may participate in tissue remodeling in the pathological mechanism of CRS.
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http://dx.doi.org/10.1016/j.clim.2021.108895DOI Listing
January 2022

CST6 protein and peptides inhibit breast cancer bone metastasis by suppressing CTSB activity and osteoclastogenesis.

Theranostics 2021 11;11(20):9821-9832. Epub 2021 Oct 11.

CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.

Bone metastasis is a frequent symptom of breast cancer and current targeted therapy has limited efficacy. Osteoclasts play critical roles to drive osteolysis and metastatic outgrowth of tumor cells in bone. Previously we identified CST6 as a secretory protein significantly downregulated in bone-metastatic breast cancer cells. Functional analysis showed that CST6 suppresses breast-to-bone metastasis in animal models. However, the functional mechanism and therapeutic potential of CST6 in bone metastasis is unknown. Using osteoclastogenesis and metastasis assays, we studied the effect and mechanism of extracellular CST6 protein in suppressing osteoclastic niches and bone metastasis of breast cancer. A number of peptides containing the functional domain of CST6 were screened to inhibit bone metastasis. The efficacy, stability and toxicity of CST6 recombinant protein and peptides were evaluated in preclinical metastasis models. We show here that CST6 inhibits osteolytic bone metastasis by inhibiting osteoclastogenesis. Cancer cell-derived CST6 enters osteoclasts by endocytosis and suppresses the cysteine protease CTSB, leading to up-regulation of the CTSB hydrolytic substrate SPHK1. SPHK1 suppresses osteoclast maturation by inhibiting the RANKL-induced p38 activation. Importantly, recombinant CST6 protein effectively suppresses bone metastasis and . We further identified several peptides mimicking the function of CST6 to suppress cancer cell-induced osteoclastogenesis and bone metastasis. Pre-clinical analyses of CTS6 recombinant protein and peptides demonstrated their potentials in treatment of breast cancer bone metastasis. These findings reveal the CST6-CTSB-SPHK1 signaling axis in osteoclast differentiation and provide a promising approach to treat bone diseases with CST6-based peptides.
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http://dx.doi.org/10.7150/thno.62187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581426PMC
October 2021

Gallic Acid Ameliorates Atopic Dermatitis-Like Skin Inflammation Through Immune Regulation in a Mouse Model.

Clin Cosmet Investig Dermatol 2021 16;14:1675-1683. Epub 2021 Nov 16.

Dermatology Hospital of Jiangxi Province, Nanchang, 330001, Jiangxi, People's Republic of China.

Background: Gallic acid (GA) has an anti-inflammatory effect by regulating inflammatory molecules. This study aimed to investigate the effect of GA on atopic dermatitis (AD)-like skin inflammation.

Methods: 4-dinitrochlorobenzene (DNCB) was used to induce an AD-like skin inflammation model. The effect of GA on DNCB-induced inflammation was assessed by measuring the thickness and histopathological examination of the ear. Serum IgE and TNF-α levels were detected. The effect of GA on lymph nodes was determined by measuring the weights and mRNA/protein expression levels of TNF-α, IL-4, IFN-γ and IL-17. Ratio of Treg cells and Th17 cells was also analyzed.

Results: It was found that the thickness and pathology of the ear were significantly improved by GA in the DNCB-induced mice. Serum IgE and TNF-α levels were significantly reduced in GA-treated model mice compared to the model group. GA treatment lowered the weight of lymph node and the expression of mRNAs of TNF-α, IL-4, IFN-γ, and IL-17 of lymph node. In the ear, inflammatory factors (IL-4, IL-5, IL-17, or IL-23) showed a significant decrease in GA-treated model mice versus model mice, while the expression levels of IL-10 and TGF-β showed a great increase in GA-treated model mice. ROR-γt showed a decrease in GA-treated model group, along with an increase expression of SOCS3.

Conclusion: GA could ameliorate AD-like skin inflammation possibly through Th17 mediated immune regulation in a DNCB-induced mouse model.
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http://dx.doi.org/10.2147/CCID.S327825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8605796PMC
November 2021

Author Correction: Long non-coding RNA NR2F1-AS1 induces breast cancer lung metastatic dormancy by regulating NR2F1 and ΔNp63.

Nat Commun 2021 Oct 7;12(1):5973. Epub 2021 Oct 7.

CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.

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http://dx.doi.org/10.1038/s41467-021-26292-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8497616PMC
October 2021

Serglycin induces osteoclastogenesis and promotes tumor growth in giant cell tumor of bone.

Cell Death Dis 2021 09 23;12(10):868. Epub 2021 Sep 23.

CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.

Giant cell tumor of bone (GCTB) is an aggressive osteolytic bone tumor characterized by the within-tumor presence of osteoclast-like multinucleated giant cells (MGCs), which are induced by the neoplastic stromal cells and lead to extensive bone destruction. However, the underlying mechanism of the pathological process of osteoclastogenesis in GCTB is poorly understood. Here we show that the proteoglycan Serglycin (SRGN) secreted by neoplastic stromal cells plays a crucial role in the formation of MGCs and tumorigenesis in GCTB. Upregulated SRGN expression and secretion are observed in GCTB tumor cells and patients. Stromal-derived SRGN promotes osteoclast differentiation from monocytes. SRGN knockdown in stromal cells inhibits tumor growth and bone destruction in a patient-derived orthotopic xenograft model of mice. Mechanistically SRGN interacts with CD44 on the cell surface of monocytes and thus activates focal adhesion kinase (FAK), leading to osteoclast differentiation. Importantly, blocking CD44 with a neutralizing antibody reduces the number of MGCs and suppresses tumorigenesis in vivo. Overall, our data reveal a mechanism of MGC induction in GCTB and support CD44-targeting approaches for GCTB treatment.
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http://dx.doi.org/10.1038/s41419-021-04161-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460728PMC
September 2021

Lactoferrin may inhibit the development of cancer via its immunostimulatory and immunomodulatory activities (Review).

Int J Oncol 2021 11 17;59(5). Epub 2021 Sep 17.

The Key Laboratory of Carcinogenesis and Cancer Invasion of The Chinese Ministry of Education, The Third Affiliated Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.

Lactoferrin (Lf) is secreted by ectodermal tissue and has a structure similar to that of transferrin. Although Lf seems to be multifunctional, its main function is related to the natural defense system of mammals. The present review aims to highlight the major actions of Lf, including the regulation of cell growth, the inhibition of toxic compound formation, the removal of harmful free radicals and its important role in immune response regulation. Moreover, Lf has antibacterial, antiviral, antioxidant, anticancer and anti‑inflammatory activities. In addition, the use of Lf for functionalization of drug nanocarriers, with emphasis on tumor‑targeted drug delivery, is illustrated. Such effects serve as an important theoretical basis for its future development and application. In neurodegenerative diseases and the brains of elderly people, Lf expression is markedly upregulated. Lf may exert an anti‑inflammatory effect by inhibiting the formation of hydroxyl free radicals. Through its antioxidant properties, Lf can prevent DNA damage, thereby preventing tumor formation in the central nervous system. In addition, Lf specifically activates the p53 tumor suppressor gene.
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http://dx.doi.org/10.3892/ijo.2021.5265DOI Listing
November 2021

Long non-coding RNA NR2F1-AS1 induces breast cancer lung metastatic dormancy by regulating NR2F1 and ΔNp63.

Nat Commun 2021 09 2;12(1):5232. Epub 2021 Sep 2.

CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.

Disseminated tumor cells often fall into a long term of dormant stage, characterized by decreased proliferation but sustained survival, in distant organs before awakening for metastatic growth. However, the regulatory mechanism of metastatic dormancy and awakening is largely unknown. Here, we show that the epithelial-like and mesenchymal-like subpopulations of breast cancer stem-like cells (BCSCs) demonstrate different levels of dormancy and tumorigenicity in lungs. The long non-coding RNA (lncRNA) NR2F1-AS1 (NAS1) is up-regulated in the dormant mesenchymal-like BCSCs, and functionally promotes tumor dissemination but reduces proliferation in lungs. Mechanistically, NAS1 binds to NR2F1 mRNA and recruits the RNA-binding protein PTBP1 to promote internal ribosome entry site (IRES)-mediated NR2F1 translation, thus leading to suppression of ΔNp63 transcription by NR2F1. Furthermore, ΔNp63 downregulation results in epithelial-mesenchymal transition, reduced tumorigenicity and enhanced dormancy of cancer cells in lungs. Overall, the study links BCSC plasticity with metastatic dormancy, and reveals the lncRNA as an important regulator of both processes.
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http://dx.doi.org/10.1038/s41467-021-25552-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413371PMC
September 2021

Pharmaco-transcriptomic correlation analysis reveals novel responsive signatures to HDAC inhibitors and identifies Dasatinib as a synergistic interactor in small-cell lung cancer.

EBioMedicine 2021 Jul 3;69:103457. Epub 2021 Jul 3.

Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, People's Republic of China. Electronic address:

Background: Histone acetylation/deacetylase process is one of the most studied epigenetic modifications. Histone deacetylase inhibitors (HDACis) have shown clinical benefits in haematological malignancies but failed in solid tumours due to the lack of biomarker-driven stratification.

Methods: We perform integrative pharmaco-transcriptomic analysis by correlating drug response profiles of five pan-HDACis with transcriptomes of solid cancer cell lines (n=659) to systematically identify generalizable gene signatures associated with HDACis sensitivity and resistance. The established signatures are then applied to identify cancer subtypes that are potentially sensitive or resistant to HDACis, and drugs that enhance the efficacy of HDACis. Finally, the reproductivity of the established HDACis signatures is evaluated by multiple independent drug response datasets and experimental assays.

Findings: We successfully delineate generalizable gene signatures predicting sensitivity (containing 46 genes) and resistance (containing 53 genes) to all five HDACis, with their reproductivity confirmed by multiple external sources and independent internal assays. Using the gene signatures, we identify low-grade glioma harbouring isocitrate dehydrogenase 1/2 (IDH1/2) mutation and non-YAP1-driven subsets of small-cell lung cancer (SCLC) that particularly benefit from HDACis monotherapy. Further, based on the resistance gene signature, we identify clinically-approved Dasatinib as a synthetic lethal drug with HDACi, synergizing in inducing apoptosis and reactive oxygen species on a panel of SCLC. Finally, Dasatinib significantly enhances the therapeutic efficacy of Vorinostat in SCLC xenografts.

Interpretation: Our work establishes robust gene signatures predicting HDACis sensitivity/resistance in solid cancer and uncovers combined Dasatinib/HDACi as a synthetic lethal combination therapy for SCLC.

Funding: This work was supported by the National Natural Science Foundation of China (82072570 to F. Yao; 82002941 to B. Sun).
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http://dx.doi.org/10.1016/j.ebiom.2021.103457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8264109PMC
July 2021

MTDH Promotes Intestinal Inflammation by Positively Regulating TLR Signalling.

J Crohns Colitis 2021 Dec;15(12):2103-2117

Pathology Tissue Bank, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Ji'nan, Shandong, China.

Macrophages in the intestinal mucosa can rapidly engage Toll-like receptor [TLR]-mediated inflammatory responses to protect against pathogen invasion, but these same innate immune responses can also drive the induction of colitis. Our previous research revealed that metadherin [MTDH] is overexpressed in multiple cancers and plays vital roles in tumour progression. However, the role of MTDH in intestinal inflammation is largely unknown. In this study, we found the MTDH expression in colonic lamina propria [CLP] macrophages was positively correlated with inflammatory colitis severity. MTDH-/- mice were protected against the symptoms of dextran sodium sulphate [DSS]-induced colitis; however, adoptive transfer of MTDH wild-type [WT] monocytes partially restored the susceptibility of MTDH-/- mice to DSS-induced colitis. TLR stimulation was sufficient to induce the expression of MTDH, whereas the absence of MTDH was sufficient to suppress TLR-induced production of inflammatory cytokines by macrophages. From a mechanistic perspective, MTDH recruited TRAF6 to TAK1, leading to TRAF6-mediated TAK1 K63 ubiquitination and phosphorylation, ultimately facilitating TLR-induced NF-κB and MAPK signalling. Taken together, our results indicate that MTDH contributes to colitis development by promoting TLR-induced pro-inflammatory cytokine production in CLP macrophages and might represent a potential therapeutic approach for intestine inflammation intervention.
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http://dx.doi.org/10.1093/ecco-jcc/jjab086DOI Listing
December 2021

BFAR coordinates TGFβ signaling to modulate Th9-mediated cancer immunotherapy.

J Exp Med 2021 07;218(7)

Chinese Academy of Sciences Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.

TGFβ is essential for the generation of anti-tumor Th9 cells; on the other hand, it causes resistance against anti-tumor immunity. Despite recent progress, the underlying mechanism reconciling the double-edged effect of TGFβ signaling in Th9-mediated cancer immunotherapy remains elusive. Here, we find that TGFβ-induced down-regulation of bifunctional apoptosis regulator (BFAR) represents the key mechanism preventing the sustained activation of TGFβ signaling and thus impairing Th9 inducibility. Mechanistically, BFAR mediates K63-linked ubiquitination of TGFβR1 at K268, which is critical to activate TGFβ signaling. Thus, BFAR deficiency or K268R knock-in mutation suppresses TGFβR1 ubiquitination and Th9 differentiation, thereby inhibiting Th9-mediated cancer immunotherapy. More interestingly, BFAR-overexpressed Th9 cells exhibit promising therapeutic efficacy to curtail tumor growth and metastasis and promote the sensitivity of anti-PD-1-mediated checkpoint immunotherapy. Thus, our findings establish BFAR as a key TGFβ-regulated gene to fine-tune TGFβ signaling that causes Th9 induction insensitivity, and they highlight the translational potential of BFAR in promoting Th9-mediated cancer immunotherapy.
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http://dx.doi.org/10.1084/jem.20202144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091105PMC
July 2021

Cathepsin C promotes breast cancer lung metastasis by modulating neutrophil infiltration and neutrophil extracellular trap formation.

Cancer Cell 2021 03 14;39(3):423-437.e7. Epub 2021 Jan 14.

CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China; Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China. Electronic address:

Lung metastasis is the major cause of breast cancer-related mortality. The neutrophil-associated inflammatory microenvironment aids tumor cells in metastatic colonization in lungs. Here, we show that tumor-secreted protease cathepsin C (CTSC) promotes breast-to-lung metastasis by regulating recruitment of neutrophils and formation of neutrophil extracellular traps (NETs). CTSC enzymatically activates neutrophil membrane-bound proteinase 3 (PR3) to facilitate interleukin-1β (IL-1β) processing and nuclear factor κB activation, thus upregulating IL-6 and CCL3 for neutrophil recruitment. In addition, the CTSC-PR3-IL-1β axis induces neutrophil reactive oxygen species production and formation of NETs, which degrade thrombospondin-1 and support metastatic growth of cancer cells in the lungs. CTSC expression and secretion are associated with NET formation and lung metastasis in human breast tumors. Importantly, targeting CTSC with compound AZD7986 effectively suppresses lung metastasis of breast cancer in a mouse model. Overall, our findings reveal a mechanism of how tumor cells regulate neutrophils in metastatic niches and support CTSC-targeting approaches for cancer treatment.
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http://dx.doi.org/10.1016/j.ccell.2020.12.012DOI Listing
March 2021

Novel Detection of Norovirus and Double Clostridium difficile in a Closed Cartridge System.

J Biomed Nanotechnol 2020 Jun;16(6):954-964

infection (CDI) has become the main cause of diarrhea-related diseases in domestic (China) inpatients. High-sensitivity and high-specificity detection methods for CDI must be applied clinically for CDI supervisory control. In this paper, we introduce a detection method for and Norovirus based on real-time PCR. We developed and optimized a primer-probe for Norovirus targets tcdA and tcdB with remarkably increased detection sensitivity. We then used this method in an integrated cassette, and found increased detection efficiency for Norovirus standards in the cassette compared to samples. These results provide a basis for further exploration of automatic testing system design.
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http://dx.doi.org/10.1166/jbn.2020.2933DOI Listing
June 2020

Genetic Fate Mapping of Transient Cell Fate Reveals N-Cadherin Activity and Function in Tumor Metastasis.

Dev Cell 2020 09 14;54(5):593-607.e5. Epub 2020 Jul 14.

State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou 510632, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China. Electronic address:

Genetic lineage tracing unravels cell fate and plasticity in development, tissue homeostasis, and diseases. However, it remains technically challenging to trace temporary or transient cell fate, such as epithelial-to-mesenchymal transition (EMT) in tumor metastasis. Here, we generated a genetic fate-mapping system for temporally seamless tracing of transient cell fate. Highlighting its immediate application, we used it to study EMT gene activity from the local primary tumor to a distant metastatic site in vivo. In a spontaneous breast-to-lung metastasis model, we found that primary tumor cells activated vimentin and N-cadherin in situ, but only N-cadherin was activated and functionally required during metastasis. Tumor cells that have ever expressed N-cadherin constituted the majority of metastases in lungs, and functional deletion of N-cad significantly reduced metastasis. The seamless genetic recording system described here provides an alternative way for understanding transient cell fate and plasticity in biological processes.
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http://dx.doi.org/10.1016/j.devcel.2020.06.021DOI Listing
September 2020

SH3RF3 promotes breast cancer stem-like properties via JNK activation and PTX3 upregulation.

Nat Commun 2020 05 19;11(1):2487. Epub 2020 May 19.

Shanghai Institute of Nutrition and Health, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Chinese Academy of Sciences, Shanghai, China.

Cancer stem-like cells (CSCs) are the tumorigenic cell subpopulation and contribute to cancer recurrence and metastasis. However, the understanding of CSC regulatory mechanisms remains incomplete. By transcriptomic analysis, we identify a scaffold protein SH3RF3 (also named POSH2) that is upregulated in CSCs of breast cancer clinical tumors and cancer cell lines, and enhances the CSC properties of breast cancer cells. Mechanically, SH3RF3 interacts with the c-Jun N-terminal kinase (JNK) in a JNK-interacting protein (JIP)-dependent manner, leading to enhanced phosphorylation of JNK and activation of the JNK-JUN pathway. Further the JNK-JUN signaling expands CSC subpopulation by transcriptionally activating the expression of Pentraxin 3 (PTX3). The functional role of SH3RF3 in CSCs is validated with patient-derived organoid culture, and supported by clinical cohort analyses. In conclusion, our work elucidates the role and molecular mechanism of SH3RF3 in CSCs of breast cancer, and might provide opportunities for CSC-targeting therapy.
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http://dx.doi.org/10.1038/s41467-020-16051-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237486PMC
May 2020

ONECUT2 overexpression promotes RAS-driven lung adenocarcinoma progression.

Sci Rep 2019 12 27;9(1):20021. Epub 2019 Dec 27.

CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

Aberrant differentiation, driven by activation of normally silent tissue-specific genes, results in a switch of cell identity and often leads to cancer progression. The underlying genetic and epigenetic events are largely unexplored. Here, we report ectopic activation of the hepatobiliary-, intestinal- and neural-specific gene one cut homeobox 2 (ONECUT2) in various subtypes of lung cancer. ONECUT2 expression was associated with poor prognosis of RAS-driven lung adenocarcinoma. ONECUT2 overexpression promoted the malignant growth and invasion of A549 lung cancer cells in vitro, as well as xenograft tumorigenesis and bone metastases of these cells in vivo. Integrative transcriptomics and epigenomics analyses suggested that ONECUT2 promoted the trans-differentiation of lung cancer cells by preferentially targeting and regulating the activity of bivalent chromatin domains through modulating Polycomb Repressive Complex 2 (PRC2) occupancy. Our findings demonstrate that ONECUT2 is a lineage-specific and context-dependent oncogene in lung adenocarcinoma and suggest that ONECUT2 is a potential therapeutic target for these tumors.
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http://dx.doi.org/10.1038/s41598-019-56277-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934839PMC
December 2019

Keratin 14-high subpopulation mediates lung cancer metastasis potentially through Gkn1 upregulation.

Oncogene 2019 09 18;38(36):6354-6369. Epub 2019 Jul 18.

State Key Laboratory of Cell Biology. Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 200031, Shanghai, China.

Metastasis is the leading cause of lung cancer-related death. Elucidating the metastasis process can provide new avenues to inhibit this malignant behavior of cancer cells. Here we found that human lung cancers with high Keratin 14 (K14) expression were associated with nodal metastasis and poor survival. Using the Kras/Trp53 lung cancer mouse model, we confirmed that K14-high cancer cells harbored increased metastatic potential. Mechanistic investigation revealed that Gastrokine 1 (Gkn1) expression positively correlated with K14 level, cancer metastasis, and poor patient survival. Importantly, ectopic expression of Gkn1 enhanced the metastatic capability of K14-low cells in vitro and in vivo, whereas knockdown of Gkn1 did the opposite, indicating the importance of Gkn1 in mediating the metastasis of K14-high cells. Further study demonstrated that Gkn1 expression conferred K14-high cells resistance to anoikis, which is critical for cancer metastasis. Collectively, our findings demonstrate that K14-high cells contribute to lung cancer metastasis potentially through inhibition of anoikis via upregulation of Gkn1.
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http://dx.doi.org/10.1038/s41388-019-0889-0DOI Listing
September 2019

Autophagy inhibition prevents glucocorticoid-increased adiposity via suppressing BAT whitening.

Autophagy 2020 03 18;16(3):451-465. Epub 2019 Jun 18.

CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.

The mechanisms underlying glucocorticoid (GC)-increased adiposity are poorly understood. Brown adipose tissue (BAT) acquires white adipose tissue (WAT) cell features defined as BAT whitening under certain circumstances. The aim of our current study was to investigate the possibility and mechanisms of GC-induced BAT whitening. Here, we showed that one-week dexamethasone (Dex) treatment induced BAT whitening, characterized by lipid droplet accumulation, in vitro and in vivo. Furthermore, autophagy and ATG7 (autophagy related 7) expression was induced in BAT by Dex, and treatment with the autophagy inhibitor chloroquine or adenovirus-mediated ATG7 knockdown prevented Dex-induced BAT whitening and fat mass gain. Moreover, Dex-increased ATG7 expression and autophagy was mediated by enhanced expression of BTG1 (B cell translocation gene 1, anti-proliferative) that stimulated activity of CREB1 (cAMP response element binding protein 1). The importance of BTG1 in this regulation was further demonstrated by the observed BAT whitening in adipocyte-specific BTG1-overexpressing mice and the attenuated Dex-induced BAT whitening and fat mass gain in mice with BTG1 knockdown in BAT. Taken together, we showed that Dex induces a significant whitening of BAT via BTG1- and ATG7-dependent autophagy, which might contribute to Dex-increased adiposity. These results provide new insights into the mechanisms underlying GC-increased adiposity and possible strategy for preventing GC-induced side effects via the combined use of an autophagy inhibitor. ACADL: acyl-Coenzyme A dehydrogenase, long-chain; ACADM: acyl-Coenzyme A dehydrogenase, medium-chain; ACADS: acyl-Coenzyme A dehydrogenase, short-chain; ADIPOQ: adiponectin; AGT: angiotensinogen; Atg: autophagy-related; BAT: brown adipose tissue; BTG1: B cell translocation gene 1, anti-proliferative; CEBPA: CCAAT/enhancer binding protein (C/EBP), alpha; CIDEA: cell death-inducing DNA fragmentation factor, alpha subunit-like effector A; CPT1B: carnitine palmitoyltransferase 1b, muscle; CPT2: carnitine palmitoyltransferase 2; CQ: chloroquine; Dex: dexamethasone; eWAT: epididymal white adipose tissue; FABP4: fatty acid binding protein 4, adipocyte; FFAs: free fatty acids; GCs: glucocorticoids; NRIP1: nuclear receptor interacting protein 1; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; PPARA: peroxisome proliferator activated receptor alpha; PPARG: peroxisome proliferator activated receptor gamma; PPARGC1A: peroxisome proliferator activated receptor, gamma, coactivator 1 alpha; PRDM16: PR domain containing 16; PSAT1: phosphoserine aminotransferase 1; RB1: RB transcriptional corepressor 1; RBL1/p107: RB transcriptional corepressor like 1; SQSTM1: sequestosome 1; sWAT: subcutaneous white adipose tissue; TG: triglycerides; UCP1: uncoupling protein 1 (mitochondrial, proton carrier); WT: wild-type.
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http://dx.doi.org/10.1080/15548627.2019.1628537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6999619PMC
March 2020

Cancer and Microenvironment Plasticity: Double-Edged Swords in Metastasis.

Trends Pharmacol Sci 2019 06 8;40(6):419-429. Epub 2019 May 8.

CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address:

Cancer initiates at one site (primary tumor) and, in most cases, spreads to other distant organs (metastasis). During the multistep process of metastasis, primary tumor cells acquire cellular and phenotypic plasticity to survive and thrive in different environments. Moreover, cancer cells also utilize and educate microenvironmental components by reshaping them into accomplices of metastasis. Recent studies have identified a plethora of new molecular and cellular modulators of metastasis that have dynamic or even opposite roles, dominating the phenotypic plasticity of both tumoral and microenvironmental components. In this review we discuss their bipotential functions and the possible underpinning mechanisms, as well as their implications for targeted cancer therapy.
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http://dx.doi.org/10.1016/j.tips.2019.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518789PMC
June 2019

Epigenetic Regulation of by Drives Metastatic Progression in Triple-Negative Breast Cancer.

Cancer Res 2019 07 2;79(13):3347-3359. Epub 2019 Apr 2.

Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan, Shandong, China.

Triple-negative breast cancer (TNBC) is highly heterogeneous and has a poor prognosis. It is therefore important to identify the underlying molecular mechanisms in order to develop novel therapeutic strategies. Although emerging research has revealed long noncoding RNAs (lncRNA) as vital to carcinogenesis and cancer progression, their functional involvement in TNBC has not been well defined. In this study, we utilized the The Cancer Genome Atlas (TCGA) database and analyzed clinical samples to show that the long noncoding antisense transcript of nicotinamide phosphoribosyltransferase (NAMPT), NAMPT-AS, is upregulated in TNBC and is associated with poor prognosis, lymph node involvement, metastasis, and advanced stage. NAMPT-AS was cotranscribed with NAMPT from a bidirectional promoter, where the distributions of H3K4me3 and H3K27Ac chromatin modifications were enriched based on ENCODE and FANTOM5, suggesting the potential enhancer-RNA characteristics of NAMPT-AS. NAMPT-AS epigenetically regulated the expression of NAMPT in two divergent ways: NAMPT-AS recruited POU2F2 to activate the transcription of NAMPT, and NAMPT-AS acted as a competing endogenous RNA to rescue NAMPT degradation from miR-548b-3p. NAMPT-AS/NAMPT promoted tumor progression and regulated autophagy through the mTOR pathway and . In a cohort of 480 breast cancer patients, NAMPT was associated with breast cancer-specific survival and overall survival. These results demonstrate that NAMPT-AS is an oncogenic lncRNA in TNBC that epigenetically activates NAMPT to promote tumor progression and metastasis. Furthermore, these data identify NAMPT-AS/NAMPT as promising therapeutic targets in patients with TNBC. SIGNIFICANCE: Upregulation of the long noncoding antisense RNA of NAMPT gene (NAMPT-AS) is associated with metastasis and poor prognosis in TNBC.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3418DOI Listing
July 2019

Cullin5 deficiency promotes small-cell lung cancer metastasis by stabilizing integrin β1.

J Clin Invest 2019 03 28;129(3):972-987. Epub 2019 Jan 28.

State Key Laboratory of Cell Biology, Innovation Center for Cell Signaling Network, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai, China.

Metastasis is the dominant cause of patient death in small-cell lung cancer (SCLC), and a better understanding of the molecular mechanisms underlying SCLC metastasis may potentially improve clinical treatment. Through genome-scale screening for key regulators of mouse Rb1-/- Trp53-/- SCLC metastasis using the pooled CRISPR/Cas9 library, we identified Cullin5 (CUL5) and suppressor of cytokine signaling 3 (SOCS3), two components of the Cullin-RING E3 ubiquitin ligase complex, as top candidates. Mechanistically, the deficiency of CUL5 or SOCS3 disrupted the functional formation of the E3 ligase complex and prevented the degradation of integrin β1, which stabilized integrin β1 and activated downstream focal adhesion kinase/SRC (FAK/SRC) signaling and eventually drove SCLC metastasis. Low expression levels of CUL5 and SOCS3 were significantly associated with high integrin β1 levels and poor prognosis in a large cohort of 128 clinical patients with SCLC. Moreover, the CUL5-deficient SCLCs were vulnerable to the treatment of the FDA-approved SRC inhibitor dasatinib. Collectively, this work identifies the essential role of CUL5- and SOCS3-mediated integrin β1 turnover in controlling SCLC metastasis, which might have therapeutic implications.
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http://dx.doi.org/10.1172/JCI122779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391098PMC
March 2019

Osteoclastogenesis Assays Using Primary Mouse Bone Marrow Cells.

Bio Protoc 2018 Jun 5;8(11):e2875. Epub 2018 Jun 5.

Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.

Osteoclasts are a group of bone-absorbing cells to degenerate bone matrix and play pivotal roles in bone growth and homeostasis. The unbalanced induction of osteoclast differentiation (osteoclastogenesis) in pathological conditions, such as osteoporosis, arthritis and skeleton metastasis of cancer, causes great pain, bone fracture, hypercalcemia or even death to patients. osteoclastogenesis analysis is useful to better understand osteoclast formation in physiological and pathological conditions. Here we summarized an easy-to-follow osteoclastogenesis protocol, which is suitable to evaluate the effect of different factors (cytokines, small molecular chemicals and conditioned medium from cell culture) on osteoclast differentiation using primary murine bone marrow cells.
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http://dx.doi.org/10.21769/BioProtoc.2875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275209PMC
June 2018

LncRNA OIP5-AS1 regulates radioresistance by targeting DYRK1A through miR-369-3p in colorectal cancer cells.

Eur J Cell Biol 2018 Jun 14;97(5):369-378. Epub 2018 Apr 14.

Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China. Electronic address:

Object: This study aimed to investigate the role of lncRNA OIP5-AS1 in regulating radioresistance of colorectal cancer (CRC) cells.

Methods: Microarray analysis was used to screen out lncRNAs differentially expressed in radio-resistant CRC cell lines. Expression levels of OIP5-AS1, miR-369-3p and DYRK1A in CRC cell lines were measured by qRT-PCR. Protein expression of DYRK1A was determined by western blot. The target relationships among OIP5-AS1, miR-369-3p and DYRK1A were validated by dual luciferase reporter assay. Impacts of OIP5-AS1 or DYRK1A on CRC cellular activity and apoptosis were investigated by MTT assay, clonogenic survival assay and flow cytometry to analyze OIP5-AS1 or DYRK1A's effect on radioresistance of CRC cells.

Results: LncRNA OIP5-AS1 and DYRK1A were down-regulated in radio-resistant CRC cell lines. OIP5-AS1 suppressed the expression of miR-369-3p, thus up-regulating DYRK1A, the downstream gene of miR-369-3p. OIP5-AS1 and DYRK1A impaired cell clonogenic survival and promoted cell apoptosis after irradiation, improving radiosensitivity of CRC cells.

Conclusion: LncRNA OIP5-AS1 suppressed cell viability, promoted radio-induced apoptosis, and enhanced the radiosensitivity of CRC cells by regulating DYRK1A expression through miR-369-3p.
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http://dx.doi.org/10.1016/j.ejcb.2018.04.005DOI Listing
June 2018

Acetylation within the N- and C-Terminal Domains of Src Regulates Distinct Roles of STAT3-Mediated Tumorigenesis.

Cancer Res 2018 06 12;78(11):2825-2838. Epub 2018 Mar 12.

Translation Medicine Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.

Posttranslational modifications of mammalian c-Src N-terminal and C-terminal domains regulate distinct functions. Myristoylation of G controls its cell membrane association and phosphorylation of Y419/Y527 controls its activation or inactivation, respectively. We provide evidence that Src-cell membrane association-dissociation and catalytic activation-inactivation are both regulated by acetylation. In EGF-treated cells, CREB binding protein (CBP) acetylates an N-terminal lysine cluster (K5, K7, and K9) of c-Src to promote dissociation from the cell membrane. CBP also acetylates the C-terminal K401, K423, and K427 of c-Src to activate intrinsic kinase activity for STAT3 recruitment and activation. N-terminal domain phosphorylation (Y14, Y45, and Y68) of STAT3 by c-Src activates transcriptionally active dimers of STAT3. Moreover, acetyl-Src translocates into nuclei, where it forms the Src-STAT3 enhanceosome for gene regulation and cancer cell proliferation. Thus, c-Src acetylation in the N-terminal and C-terminal domains play distinct roles in Src activity and regulation. CBP-mediated acetylation of lysine clusters in both the N-terminal and C-terminal regions of c-Src provides additional levels of control over STAT3 transcriptional activity. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-2314DOI Listing
June 2018

Biomarker Studies in Early Detection and Prognosis of Breast Cancer.

Adv Exp Med Biol 2017 ;1026:27-39

Chinese Academy of Sciences, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai, China.

Breast cancer is characterized with enormous heterogeneity, which represents the major hurdle for accurate diagnosis and curative therapy. It is generally believed that genome unstability and molecular evolvability underlie the robustness of cancer cells in hostile microenvironment and their resilience to therapeutic intervention. Conventional histopathological classification of breast cancer falls short of providing sufficient prognostic and predictive power, and thus biomarkers indicative of tumor intrinsic features at molecular levels have been actively pursued in biomedical researches. Currently, a number of molecular biomarkers are being used in standard clinical practice, including the hormone receptors for breast cancer subtyping and several genes involved in genome maintenance for prediction of breast cancer susceptibility. In addition, a number of biomarkers of single genes or multigene signatures have been approved for clinical use for breast cancer prognosis. A growing body of molecular biomarkers are being studied and tested to facilitate disease diagnosis and management, especially for breast cancer early detection, accurate prediction of metastatic behaviors, and selection of therapy. However, most of them are still at the preclinical stages. Finally, biomarkers of noninvasive protocols, such as serological molecules, have advantages in detection convenience over other biomarker types and therefore are of particular interest in translational and clinical development to improve diagnosis, prognosis, and treatment.
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http://dx.doi.org/10.1007/978-981-10-6020-5_2DOI Listing
July 2018
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