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Primary cilia are microtubule-based organelles that mediate various biological processes. Pancreatic cells are typically ciliated; however, the role of primary cilia in acute pancreatitis (AP) is largely unknown. Here, we report that the loss of primary cilia, mediated by SHCBP1 (SHC1 binding protein), exerted a provocative effect on AP. Primary cilia are extensively lost in inflamed pancreatic cells in vitro and in mouse tissues with AP in vivo. Abrogation of primary cilia aggravated lipopolysaccharide (LPS)-induced inflammation in pancreatic cells. Mechanistically, AP induced the overexpression of SHCBP1 mitotic factor, which is localized to the base of primary cilia. SHCBP1 deficiency relieved LPS- and cerulein-induced pancreatitis by preventing the loss of primary cilia in vitro and in vivo. Collectively, we reveal that inflammation-induced loss of primary cilia aggravates AP. Furthermore, abrogating SHCBP1 to prevent primary cilia loss is an efficient strategy to combat AP. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PC) is a highly aggressive and deadly malignancy with limited treatment options and poor prognosis. Identifying new therapeutic targets and developing effective strategies for PC treatment is of utmost importance. Here, we revealed that SHCBP1 is significantly overexpressed in PC and negatively correlated with patient prognosis. Knockout of SHCBP1 inhibits the proliferation and migration of PC cells in vitro, and suppresses the tumor growth in vivo. In addition, we identified AZD5582 as a novel inhibitor of SHCBP1, which efficiently restrains the growth of PC in cell lines, organoids, and patient‐derived xenografts. Mechanistically, we found that AZD5582 induced the apoptosis of PC cells by inhibiting the activity of PI3K/AKT signaling and preventing the degradation of TP53. Collectively, our study highlights SHCBP1 as a potential therapeutic target and its inhibitor AZD5582 as a viable agent for PC treatment strategies. [ABSTRACT FROM AUTHOR]

Abstract Background Malignant tumours seriously threaten human life and health, and effective treatments for cancer are still being explored. The ability of SHC SH2 domain-binding protein 1 (SHCBP1) to induce cell cycle disturbance and inhibit tumour growth has been increasingly studied, but its dynamic role in the tumour cell cycle and corresponding effects leading to mitotic catastrophe and DNA damage have rarely been studied. Results In this paper, we found that the nucleoprotein SHCBP1 exhibits dynamic spatiotemporal expression during the tumour cell cycle, and SHCBP1 knockdown slowed cell cycle progression by inducing spindle disorder, as reflected by premature mitotic entry and multipolar spindle formation. This dysfunction was caused by G2/M checkpoint impairment mediated by downregulated WEE1 kinase and NEK7 (a member of the mammalian NIMA-related kinase family) expression and upregulated centromere/kinetochore protein Zeste White 10 (ZW10) expression. Moreover, both in vivo and in vitro experiments confirmed the significant inhibitory effects of SHCBP1 knockdown on tumour growth. Based on these findings, SHCBP1 knockdown in combination with low-dose DNA-damaging agents had synergistic tumouricidal effects on tumour cells. In response to this treatment, tumour cells were forced into the mitotic phase with considerable unrepaired DNA lesions, inducing mitotic catastrophe. These synergistic effects were attributed not only to the abrogation of the G2/M checkpoint and disrupted spindle function but also to the impairment of the DNA damage repair system, as demonstrated by mass spectrometry-based proteomic and western blotting analyses. Consistently, patients with low SHCBP1 expression in tumour tissue were more sensitive to radiotherapy. However, SHCBP1 knockdown combined with tubulin-toxic drugs weakened the killing effect of the drugs on tumour cells, which may guide the choice of chemotherapeutic agents in clinical practice. Conclusion In summary, we elucidated the role of the nucleoprotein SHCBP1 in tumour cell cycle progression and described a novel mechanism by which SHCBP1 regulates tumour progression and through which targeting SHCBP1 increases sensitivity to DNA-damaging agent therapy, indicating its potential as a cancer treatment. Graphical Abstract

Papillary thyroid carcinoma (PTC) is the most common thyroid cancer with a rapidly increasing incidence globally. Bioinformatics analyses suggested that SHCBP1 (SHC SH2 Domain-Binding Protein 1) was significantly up-regulated in PTC tumor tissues, which was further confirmed by immunohistochemical staining and qPCR analyses in Xuzhou cohort. Moreover, the results indicated that the mRNA level of SHCBP1 was negatively associated with patients' disease-free survival rate, and further analysis reveals that patients with high SHCBP1 expression tend to have more lymph node metastasis. Afterward, MTT, colony formation, cell-cycle assay, FACS apoptosis assay, invasion, migration, as well as scratch assay were performed to study the phenotypes change of PTC cells after knocking down SHCBP1. The in vivo subcutaneous tumor model was developed to study the proliferation ability of PTC cells after SHCBP1 knockdown. We show that knock down of SHCBP1 significantly inhibits PTC cell proliferation, cell cycle, invasion and migration in vivo and in vitro. Western blot and qRT-PCR showed that knockdown of SHCBP1 could significantly reduce MYC, KLF4, CD44, ITGA6, ITGB1, ITGB5, and COL4A2 expression at both RNA and protein levels, which indicated that SHCBP1 might be involved in PTC carcinogenesis and progression through targeting formation of integrin and collagen and cell stemness pathways, and can be a potential diagnosis biomarker and therapeutic target for PTC. [ABSTRACT FROM AUTHOR]

Background: Malignant tumours seriously threaten human life and health, and effective treatments for cancer are still being explored. The ability of SHC SH2 domain-binding protein 1 (SHCBP1) to induce cell cycle disturbance and inhibit tumour growth has been increasingly studied, but its dynamic role in the tumour cell cycle and corresponding effects leading to mitotic catastrophe and DNA damage have rarely been studied. Results: In this paper, we found that the nucleoprotein SHCBP1 exhibits dynamic spatiotemporal expression during the tumour cell cycle, and SHCBP1 knockdown slowed cell cycle progression by inducing spindle disorder, as reflected by premature mitotic entry and multipolar spindle formation. This dysfunction was caused by G2/M checkpoint impairment mediated by downregulated WEE1 kinase and NEK7 (a member of the mammalian NIMA-related kinase family) expression and upregulated centromere/kinetochore protein Zeste White 10 (ZW10) expression. Moreover, both in vivo and in vitro experiments confirmed the significant inhibitory effects of SHCBP1 knockdown on tumour growth. Based on these findings, SHCBP1 knockdown in combination with low-dose DNA-damaging agents had synergistic tumouricidal effects on tumour cells. In response to this treatment, tumour cells were forced into the mitotic phase with considerable unrepaired DNA lesions, inducing mitotic catastrophe. These synergistic effects were attributed not only to the abrogation of the G2/M checkpoint and disrupted spindle function but also to the impairment of the DNA damage repair system, as demonstrated by mass spectrometry-based proteomic and western blotting analyses. Consistently, patients with low SHCBP1 expression in tumour tissue were more sensitive to radiotherapy. However, SHCBP1 knockdown combined with tubulin-toxic drugs weakened the killing effect of the drugs on tumour cells, which may guide the choice of chemotherapeutic agents in clinical practice. Conclusion: In summary, we elucidated the role of the nucleoprotein SHCBP1 in tumour cell cycle progression and described a novel mechanism by which SHCBP1 regulates tumour progression and through which targeting SHCBP1 increases sensitivity to DNA-damaging agent therapy, indicating its potential as a cancer treatment. [ABSTRACT FROM AUTHOR]

Src homolog and collagen homolog binding protein 1 (SHCBP1) binds to the SH2 domain of SHC‐transforming protein 1 (SHC1) and is involved in midbody organization and cytokinesis completion. SHCBP1 has been reported to be a cancer driver gene, promoting cancer progression. However, the functional role and underlying mechanism of SHCBP1 in regulating lung adenocarcinoma (LUAD) cell proliferation and migration are incompletely understood. Here, we discovered that SHCBP1 is overexpressed in LUAD tissues and is associated with a poor prognosis. SHCBP1 knockdown inhibited LUAD cell proliferation and migration by arresting the cell cycle and preventing epithelial–mesenchymal transition (EMT) via decreasing cyclin‐dependent kinase 1 (CDK1) expression. Mechanistically, CDK1 overexpression reversed SHCBP1 knockdown‐induced inhibition of proliferation and migration, confirming CDK1 as a key downstream target of SHCBP1. In addition, we proposed that rucaparib may be a small‐molecule inhibitor of SHCBP1 and validated both in vitro and in vivo that rucaparib inhibits cell proliferation and migration via suppression of the SHCBP1/CDK1 pathway in LUAD. Our study elucidates a newly identified role of SHCBP1 in promoting cell proliferation and migration in LUAD, and suggests rucaparib as a potential inhibitor for LUAD treatment. [ABSTRACT FROM AUTHOR]

Objective: To analyze the expression and clinical significance of SHC SH2-binding protein 1 (SHCBP1) in lung adenocarcinoma (LUAD). Methods: Oncomine, TIMER, UALCAN, GEPIA, Kaplan-Meier plotter and STRING databases were used to explore the effect of SHCBP1 on progression and immune infiltration of LUAD. Results: Expression of SHCBP1 mRNA in LUAD tissue was significantly higher than that in normal lung tissue (P<0.05). Expression of SHCBP1 mRNA was significantly increased in LUAD patients with smoking history, nodal metastasis, late clinical stage and TP53 mutation (P<0.05). Survival analysis by GEPIA and Kaplan-Meier plotter databases showed that LUAD patients with high SHCBP1 mRNA expression had a lower overall survival rate (P<0.05). SHCBP1 mRNA was correlated with immune cell infiltration, immune cell markers and immune checkpoint expression in LUAD. Conclusion: High expression of SHCBP1 is related to poor prognosis and tumor immune infiltration of LUAD patients. [ABSTRACT FROM AUTHOR]

Melanoma originates from the malignant mutational transformation of melanocytes in the basal layer of the epidermal layer of the skin. It can easily spread and metastasize in the early stage, resulting in a poor prognosis. Therefore, it is particularly important to find effective antitumor adjuvant drugs to inhibit the occurrence and development of melanoma. In this study, we found that resveratrol, a polyphenolic compound from grape plants, can significantly inhibit the proliferation, colony formation and migration of mouse melanoma B16 cells. Notably, resveratrol was also found to inhibit the expression of SHCBP1 in B16 cells. Transcriptional analysis and cellular studies showed that SHCBP1 can activate the MAPK/ERK signaling pathway to regulate cyclin expression and promote the G1/S phase transition of the cell cycle by upregulating ERK1/2 phosphorylation levels. Resveratrol further downregulates the phosphorylation level of ERK1/2 by inhibiting SHCBP1 expression, thus inhibiting tumor cell proliferation. In conclusion, resveratrol inhibits the proliferation of B16 cells by regulating the ERK1/2 signaling pathway through SHCBP1. As an upstream protein of the ERK1/2 signaling pathway, SHCBP1 may be involved in the process of resveratrol-mediated inhibition of tumor cell proliferation. [ABSTRACT FROM AUTHOR]

SHCBP1 (Shc SH2-domain binding protein 1) is a member of the Src and collagen homolog (Shc) protein family and is closely associated with multiple signaling pathways that play important roles during hair follicle induction, morphogenesis, and cycling. The purpose of this study was to investigate SHCBP1 gene expression, polymorphisms, and the association between SHCBP1 and wool quality traits in Chinese Merino sheep. The SHCBP1 gene was shown, by qPCR, to be ubiquitously expressed in sheep tissues and differentially expressed in the adult skin of Chinese Merino and Suffolk sheep. Four SNPs (termed SHCBP1SNPs 1–4) were identified by Sanger sequencing and were located in exon 2, intron 9, intron 12, and exon 13 of the sheep SHCBP1 gene, respectively. SHCBP1SNPs 3 and 4 (rs411176240 and rs160910635) were significantly associated with wool crimp (P < 0.05). The combined polymorphism (SHCBP1SNP3-SHCBP1SNP4) was significantly associated with wool crimp (P < 0.05). Bioinformatics analysis showed that the SNPs associated with wool crimp (SHCBP1SNPs 3 and 4) might affect the pre-mRNA splicing by creating binding sites for serine–arginine-rich proteins and that SHCBP1SNP4 might alter the SHCBP1 mRNA and protein secondary structure. Our results suggest that SHCBP1 influences wool crimp and SHCBP1SNPs 3 and 4 might be useful markers for marker-assisted selection and sheep breeding. [ABSTRACT FROM AUTHOR]

The incidence of cancer is increasing globally, and it is the most common cause of death. The identification of novel cancer diagnostic and prognostic biomarkers is important for developing cancer treatment strategies and reducing mortality. SHCSH2 domain-binding protein 1 (SHCBP1) is a protein that specifically binds to the SH2 domain of Src homology–collagen. It participates in the regulation of a variety of signal transduction pathways and can activate a variety of signaling molecules to perform a series of physiological functions. SHCBP1 is expressed in a variety of human tissues, but its abnormal expression in various systems is associated with cancer. SHCBP1 is abnormally expressed in a variety of tumors, and plays roles in almost all aspects of cancer biology (such as cell proliferation, apoptosis prevention, invasion, and metastasis) through various possible mechanisms. Its expression level is related to the clinicopathological characteristics of patients. In addition, the SHCBP1 expression pattern is closely related to cancer type, stage, and other clinical variables. Therefore, SHCBP1 is a promising tumor biomarker for cancer diagnosis and prognosis and a potential therapeutic target. This article reviews the expression, biological functions, mechanisms, and potential clinical significance of SHCBP1 in various human tumors to provide a new theoretical basis for clinical molecular diagnosis, molecular targeted therapy, and scientific research on cancer.

Melanoma originates from the malignant mutational transformation of melanocytes in the basal layer of the epidermal layer of the skin. It can easily spread and metastasize in the early stage, resulting in a poor prognosis. Therefore, it is particularly important to find effective antitumor adjuvant drugs to inhibit the occurrence and development of melanoma. In this study, we found that resveratrol, a polyphenolic compound from grape plants, can significantly inhibit the proliferation, colony formation and migration of mouse melanoma B16 cells. Notably, resveratrol was also found to inhibit the expression of SHCBP1 in B16 cells. Transcriptional analysis and cellular studies showed that SHCBP1 can activate the MAPK/ERK signaling pathway to regulate cyclin expression and promote the G1/S phase transition of the cell cycle by upregulating ERK1/2 phosphorylation levels. Resveratrol further downregulates the phosphorylation level of ERK1/2 by inhibiting SHCBP1 expression, thus inhibiting tumor cell proliferation. In conclusion, resveratrol inhibits the proliferation of B16 cells by regulating the ERK1/2 signaling pathway through SHCBP1. As an upstream protein of the ERK1/2 signaling pathway, SHCBP1 may be involved in the process of resveratrol-mediated inhibition of tumor cell proliferation.

Shc SH2-domain binding protein 1 (SHCBP1), a protein specific binding to SH2 domain of Src homolog and collagen homolog (Shc), takes part in the regulation of various signal transduction pathways, which has been reported to be associated with tumorigenesis and progression. However, the pathological mechanisms are not completely investigated. Thus, this study aimed to comprehensively elucidate the potential functions of SHCBP1 in multiple cancer types. The comprehensive analyses for SHCBP1 in various tumors, including gene expression, diagnosis, prognosis, immune-related features, genetic alteration, and function enrichment, were conducted based on multiple databases and analysis tools. SHCBP1 was upregulated in most types of cancers. The results of qRT-PCR had confirmed that SHCBP1 mRNA was significantly upregulated in lung adenocarcinoma (LUAD) and liver hepatocellular carcinoma (LIHC) cell lines. Based on the receiver operating characteristic (ROC) and survival analysis, SHCBP1 was considered as a potential diagnostic and prognostic biomarker. Furthermore, SHCBP1 expression was linked with tumor immunity and immunosuppressive microenvironment according to the correlation analysis of SHCBP1 expression with immune cells infiltration, immune checkpoint genes, and immune-related genes (MHC genes, chemokines, and chemokines receptors). Moreover, SHCBP1 expression correlated with tumor mutational burden (TMB), microsatellite instability (MSI), and neoantigens. The feature of SHCBP1 mutational landscape in pan-cancer was identified. Finally, we focused on investigating the clinical significance and the potential biological role of SHCBP1 in LUAD. Our study comprehensively uncovered that SHCBP1 could be identified as an immune-related biomarker for cancer diagnosis and prognosis, and a potential therapeutic target for tumor immunotherapy.

Adenocarcinoma of the esophagogastric junction (AEG) has received widespread attention because of its increasing incidence. However, the molecular mechanism underlying tumor progression remains unclear. Here, we report that the downregulation of Ubiquitin-specific peptidase 49 (USP49) promotes ferroptosis in OE33 and OE19 cells, thereby inhibiting cell proliferation in vitro and in vivo, whereas the overexpression of USP49 had the opposite effect. In addition, USP49 downregulation promoted AEG cell radiotherapy sensitivity. Moreover, overexpression of Glutathione PeroXidase 4 (GPX4) reversed the ferroptosis and proliferation inhibition induced by USP49 knockdown. Mechanistically, USP49 deubiquitinates and stabilizes Shc SH2-domain binding protein 1 (SHCBP1), subsequently facilitating the entry of β-catenin into the nucleus to enhance GPX4 transcriptional expression. Finally, high USP49 expression was correlated with shorter overall survival in patients with AEG. In summary, our findings identify USP49 as a novel regulator of ferroptosis in AEG cells, indicating that USP49 may be a potential therapeutic target in AEG., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Cancer genomes are characterized by the accumulation of small-scale somatic mutations as well as large-scale chromosomal deletions, amplifications, and complex structural rearrangements. This characteristic is at least partially dependent on the ability of cancer cells to undergo recurrent chromosome breakage. In order to address the extent to which chromosomal structural rearrangement breakpoints correlate with recurrent DNA double-strand breaks (DSBs), we simultaneously mapped chromosome structural variation breakpoints (using whole-genome DNA-seq) and spontaneous DSB formation (using Break-seq) in the estrogen receptor (ER)-positive breast cancer cell line MCF-7 and a non-cancer control breast epithelium cell line MCF-10A. We identified concurrent DSBs and structural variation breakpoints almost exclusively in the pericentromeric region of chromosome 16q in MCF-7 cells. We fine-tuned the identification of copy number variation breakpoints on 16q. In addition, we detected recurrent DSBs that occurred in both MCF-7 and MCF-10A. We propose a model for DSB-driven chromosome rearrangements that lead to the translocation of 16q, likely with 10q, and the eventual 16q loss that does not involve the pericentromere of 16q. We present evidence from RNA-seq data that select genes, including SHCBP1, ORC6, and MYLK3, which are immediately downstream from the 16q pericentromere, show heightened expression in MCF-7 cell line compared to the control. Data published by The Cancer Genome Atlas show that all three genes have increased expression in breast tumor samples. We found that SHCBP1 and ORC6 are both strong poor prognosis and treatment outcome markers in the ER-positive breast cancer cohort. We suggest that these genes are potential oncogenes for breast cancer progression. The search for tumor suppressor loss that accompanies the 16q loss ought to be augmented by the identification of potential oncogenes that gained expression during chromosomal rearrangements. [ABSTRACT FROM AUTHOR]

Background: This study aimed to explore the functional roles of Shc SH2‐domain‐binding protein 1 (SHCBP1) and Kinesin Family Member 23 (KIF23) in HPV‐negative head and neck squamous cell carcinoma (HNSCC). Methods: Bioinformatic analysis was conducted using data from The Cancer Genome Atlas (TCGA) and GSE103322. HNSCC cell lines were used for in vitro and in vivo analysis. Results: SHCBP1 upregulation was associated with unfavorable survival. SHCBP1 knockdown reduced cell proliferation and increased the cisplatin sensitivity of SCC9/SCC25 cells. SHCBP1 interacted with KIF23 via its Nesd homology domain (NHD) domain, which was important for its nucleus localization. SHCBP1 positively modulated KIF23 expression and activated phosphoinositide 3‐kinase (PI3K)/protein kinase B (Akt), extracellular signal regulated kinase (ERK)1/2, nuclear factor kappa B (NF/κB)‐p65, and Wnt/β‐catenin signaling. KIF23 knockdown abrogated cisplatin resistance induced by SHCBP1 overexpression. Conclusion: SHCBP1 interacts with KIF23 and cooperatively regulates cell‐cycle progression and cisplatin resistance of HNSCC tumor cells. [ABSTRACT FROM AUTHOR]

O-GlcNAcylation is important in the development and progression of pancreatic ductal adenocarcinoma (PDAC). The glycosyltransferase EGF domain-specific O-linked GlcNAc transferase (EOGT) acts as a key participant in glycosylating NOTCH1. High-throughput sequencing of specimens from 30 advanced PDAC patients identified SHCBP1 and EOGT as factors of poor prognosis. We hypothesized that they could mediate PDAC progression by influencing NOTCH1 O-GlcNAcylation. Thus, 186 PDAC tissue specimens were immunostained for EOGT and SHCBP1. Pancreatic cancer cell lines and nude mouse models were used for in vitro and in vivo experiments. Respectively, The protein expression of EOGT and SHCBP1 was significantly elevated and correlated with worse prognosis in PDAC patients. In vitro, SHCBP1 overexpression promoted pancreatic cancer cell proliferation, migration and invasion, while knocking down SHCBP1 and EOGT inhibited these malignant processes. In vivo data showed that SHCBP1 overexpression promoted xenograft growth and lung metastasis and shortened survival in mice, whereas knocking down either EOGT or SHCBP1 expression suppressed xenograft growth and metastasis and prolonged survival. We further clarified the molecular mechanisms by which EOGT and SHCBP1 enhance the O-GlcNAcylation of NOTCH1, Subsequently promoting the nuclear localization of the Notch intracellular domain (NICD) and inhibiting the transcription of E-cadherin and P21 in pancreatic cancer cells. [ABSTRACT FROM AUTHOR]

Papillary thyroid carcinoma (PTC) is the most common thyroid cancer with a rapidly increasing incidence globally. Bioinformatics analyses suggested that SHCBP1 (SHC SH2 Domain-Binding Protein 1) was significantly up-regulated in PTC tumor tissues, which was further confirmed by immunohistochemical staining and qPCR analyses in Xuzhou cohort. Moreover, the results indicated that the mRNA level of SHCBP1 was negatively associated with patients’ disease-free survival rate, and further analysis reveals that patients with high SHCBP1 expression tend to have more lymph node metastasis. Afterward, MTT, colony formation, cell-cycle assay, FACS apoptosis assay, invasion, migration, as well as scratch assay were performed to study the phenotypes change of PTC cells after knocking down SHCBP1. The in vivo subcutaneous tumor model was developed to study the proliferation ability of PTC cells after SHCBP1 knockdown. We show that knock down of SHCBP1 significantly inhibits PTC cell proliferation, cell cycle, invasion and migration in vivo and in vitro. Western blot and qRT-PCR showed that knockdown of SHCBP1 could significantly reduce MYC, KLF4, CD44, ITGA6, ITGB1, ITGB5, and COL4A2 expression at both RNA and protein levels, which indicated that SHCBP1 might be involved in PTC carcinogenesis and progression through targeting formation of integrin and collagen and cell stemness pathways, and can be a potential diagnosis biomarker and therapeutic target for PTC.

Papillary thyroid carcinoma (PTC) is the most common thyroid cancer with a rapidly increasing incidence globally. Bioinformatics analyses suggested that SHCBP1 (SHC SH2 Domain-Binding Protein 1) was significantly up-regulated in PTC tumor tissues, which was further confirmed by immunohistochemical staining and qPCR analyses in Xuzhou cohort. Moreover, the results indicated that the mRNA level of SHCBP1 was negatively associated with patients' disease-free survival rate, and further analysis reveals that patients with high SHCBP1 expression tend to have more lymph node metastasis. Afterward, MTT, colony formation, cell-cycle assay, FACS apoptosis assay, invasion, migration, as well as scratch assay were performed to study the phenotypes change of PTC cells after knocking down SHCBP1. The in vivo subcutaneous tumor model was developed to study the proliferation ability of PTC cells after SHCBP1 knockdown. We show that knock down of SHCBP1 significantly inhibits PTC cell proliferation, cell cycle, invasion and migration in vivo and in vitro. Western blot and qRT-PCR showed that knockdown of SHCBP1 could significantly reduce MYC, KLF4, CD44, ITGA6, ITGB1, ITGB5, and COL4A2 expression at both RNA and protein levels, which indicated that SHCBP1 might be involved in PTC carcinogenesis and progression through targeting formation of integrin and collagen and cell stemness pathways, and can be a potential diagnosis biomarker and therapeutic target for PTC. [ABSTRACT FROM AUTHOR]

Long non-coding RNA (lncRNA) TP53 target 1 (TP53TG1) is known to be strongly associated with tumor and cancer progression. However, its expression profile, unique role, and regulatory pathways in retinoblastoma (RB) are not known. Here, we revealed a large expression of TP53TG1 in RB tissues and cell lines. Conversely, we showed marked suppression of cell proliferation, migration, and invasion in TP53TG1 knocked down RB cells. Mechanistically, we established that TP53TG1 directly interacted with microRNA (miR)-33b in RB cells. Furthermore, TP53TG1 transcripts were found to be inversely correlated with miR-33b in RB tissues. We also showed that miR-33b suppression partly reversed the TP53TG1 knockdown mediated effects on tumor biology. Finally, TP53TG1 was shown to modulate the levels of SHC Binding and Spindle Associated 1 (SHCBP1), a direct target of miR-33b in RB cells. Based on the above data, we propose that TP53TG1 regulates RB progression via its modulation of the miR-33b/SHCBP1 pathway. [ABSTRACT FROM AUTHOR]

The crucial role of cancer-associated fibroblasts (CAFs) in promoting T-cell exclusion has a significant impact on tumor immune evasion and resistance to immunotherapy. Therefore, enhancing T-cell infiltration into solid tumors has emerged as a pivotal area of research. We achieved a conventional knockout of Shcbp1 (Shcbp1 -/- ) through CRISPR/Cas9 gene editing and crossed these mice with spontaneous breast cancer MMTV-PyMT mice, resulting in PyMT Shcbp1 -/- mice. The different CAF subtypes were detected by flow cytometry analysis (FCA). We evaluated collagen and CAFs levels using Sirius red staining, immunohistochemistry (IHC), and immunofluorescence (IF). Primary tumor cells and CAFs were isolated from both PyMT Shcbp1 +/+ and PyMT Shcbp1 -/- mice. We analyzed CAFs' proliferation, invasion, migration, apoptosis, and cell cycle. Transwell coculture experiments were performed with primary tumor cells and CAFs to evaluate the role of CAFs in increasing the sensitivity of tumor cells to Erdafitinib. Tumors from PyMT Shcbp1 +/+ and PyMT Shcbp1 -/- mice were orthotopically transplanted to assess the therapeutic effect of the Erdafitinib and PD-1 combination. CAFs and T-cell infiltration in these tumors were assessed using FCA and IF. Knockout of Shcbp1 leads to a significant reduction in tumor burden, promotes longer survival, and decreases CAFs in MMTV-PyMT. Moreover, knockout of Shcbp1 enhances the sensitivity of Erdafitinib, leading to effective inhibition of CAFs' proliferation and invasion, as well as the induction of apoptosis. Additionally, it results in cell cycle arrest at the G2/M phase in vitro. Meanwhile, Shcbp1 -/- CAFs change the sensitivity of Shcbp1 -/- tumor cells to Erdafitinib compared to Shcbp1 +/+ CAFs. Importantly, knockout of Shcbp1 boosts the effectiveness of Erdafitinib in combination with immune checkpoint blockade therapy by augmenting T-cell infiltration through CAFs regulation in vivo. Our findings demonstrate that knockout of Shcbp1 holds significant potential in enhancing the therapeutic response of Erdafitinib combined with PD-1 antibody treatment, offering promising prospects for future breast cancer therapies., (© 2024 Wiley Periodicals LLC.)

Long noncoding RNAs (lncRNAs) have been shown to have critical regulatory roles in tumorigenesis. lncRNA LINC01561 (LINC01561) is a newly identified tumor‐related lncRNA and its dysregulation has been demonstrated in several tumors. However, whether LINC01561 is involved in the progression of non‐small‐cell lung carcinoma (NSCLC) and its underlying mechanisms remain unknown. In this study, we first provided evidence that LINC01561 expressions were distinctly upregulated in NSCLC tissues and cell lines. Combining with bioinformatics assays and mechanism experiments, our group demonstrated that LINC01561 was activated by SOX2 in NSCLC. Clinical research revealed that upregulation of LINC01561 was related to poorer clinicopathologic features and shorter survival time. Functionally, suppression of LINC01561 exhibited tumor‐suppressive functions through impairing cell proliferation, migration, and invasion as well as inducing apoptosis. Moreover, we verified that LINC01561 could directly bind to miR‐760, isolating miR‐760 from its target gene SHC SH2 domain‐binding protein 1 (SHCBP1). We also found that SHCBP1 was lowly expressed in NSCLC and served as a tumor promoter. A functional study indicated that LINC01561 regulated SHCBP1 expression by competitively binding to miR‐760. In summary, our findings indicated that SOX2‐induced overexpression of LINC01561 promoted the proliferation and metastasis by acting as a competing endogenous RNA to modulate SHCBP1 by sponging miR‐760. [ABSTRACT FROM AUTHOR]

Objective: Prostate cancer (PCa) is an aggressive tumor. SHC SH2-domain-binding protein 1 (SHCBP1) has been identified frequently upregulated in various cancers, in addition to PCa. The aims of this study were to determine the relationships between SHCBP1 and clinicopathological characteristics of PCa and to explore the role of SHCBP1 in PCa proliferation and progression. Methods: Tissue microarray and immunohistochemistry were used to determine the prognostic significance of SHCBP1. The relationship between clinicopathological characteristics of PCa and SHCBP1 was then analyzed using Cox regression analyses. To investigate SHCBP1 functions in vitro and in vivo, we knocked down SHCBP1 in PCa cell lines and established xenograft mice models. A series of cytological function assays were utilized to determine the role of SHCBP1 in cell proliferation, migration, invasion, and apoptosis. Results: SHCBP1 was significantly upregulated in PCa tissues compared with BPH tissues. Patients with a higher expression of SHCBP1 were associated with poor survival outcomes than those with a lower expression of SHCBP1. Lentivirus-mediated shRNA knockdown of SHCBP1 in prostate cancer cell lines diminished cell growth, migration, and invasion dramatically both in vitro and in vivo, accompanied by an enhanced expression of large tumor suppressor 1 (LATS1) and tumor protein P53 (TP53) and inhibition of MDM2 proto-oncogene (MDM2), which suggested that SHCBP1 may promote proliferation and invasion in vitro via the LATS1–MDM2–TP53 pathway. The results of cycloheximide (CHX) and MG-132 assays indicated that SHCBP1 knockdown could attenuate the degradation of TP53 by the proteasome, prolong the half-life of TP53, and enhance the stabilization of TP53. Conclusion: These findings suggest that SHCBP1 overexpression contributes to PCa progression and that targeting SHCBP1 might be therapeutically beneficial to patients with PCa. [ABSTRACT FROM AUTHOR]

To investigate the expression characteristics and prognostic value of SHCBP1 in breast cancer and its relevant subtypes, the Oncomine, bc-GenExMiner v4.2, Kaplan-Meier plotter, GSE41994, and STRING databases were used to analyze the mRNA expression level of SHCBP1 in breast cancer patients and its correlation with their survival rate. Results show that: ( 1) The mRNA level of SHCBP1 in breast cancer tissues was significantly higher than that of normal tissue samples, but the expression level of SHCBP1 in breast cancer patients with different molecular subtypes was different; (2) Increased expression of SHCBP1 might lead to shorter distant metastasis-free survival (DMFS) and disease-free survival (DFS) of Luminal A subtype; (3) In patients with ER(+), PR(+) subtype, chemo-adjuvant only, ER ( + ) with chemo-adjuvant therapy, endocrine therapy-include, and endocrine therapy-exclude breast cancer, elevated SHCBP1 expression significantly correlated with shorten relapse-free survival rate (RFS) ; (4) SHCBP1 and CDC45 mRNA expression levels were positively correlated and SHCBP1 might interact with 10 proteins such as KIF23. Therefore, SHCBP1 may be a promising prognostic indicator and therapeutic target for breast cancer. [ABSTRACT FROM AUTHOR]

Abstract Background Our previous studies reported that SHC SH2-domain binding protein 1 (SHCBP1) functions as an oncogene via promoting cell proliferations in synovial sarcoma (SS) cells. However, whether SHCBP1 has any effect on tumor metastasis remains unexplored. Methods The expression of SHCBP1 was analyzed in 76 SS tissues and two SS cell lines by immunohistochemistry and real-time RT-PCR. The relationship between SHCBP1 expression and the clinicopathological features of SS was investigated. The role of SHCBP1 in SS cell adhesion, migration, invasion and angiogenesis was explored by adhesion, Wound healing, Transwell, and Matrigel tube formation assays. Western blotting was conducted to detect the protein expressions of TGF-β1/Smad signaling pathway and EMT-related markers. The key molecules associated with migration, invasion and EMT were evaluated by immunohistochemistry in tumor specimens. Results In current study, we demonstrated that SHCBP1 overexpression significantly enhanced adhesion, migration, invasion and angiogenesis of SS cells. In contrast, SHCBP1 knockdown elicited the opposite effects on these phenotypes in vitro. SHCBP1 promoted tumor metastasis through inducing epithelial-mesenchymal transition (EMT) in SS cells. SHCBP1 knockdown could block the incidence of metastasis and EMT in SS cells. Furthermore, transforming growth factor-β1 (TGF-β1) induced SHCBP1 expression in a time-dependent pattern and SHCBP1 knockdown inhibited TGF-β1-induced EMT. The activation of the TGF-β1/Smad signaling pathway was involved in the oncogenic functions of SHCBP1 in SS. In addition, high expression of SHCBP1 in SS patients was associated with tumor progression and decreased survival as well as poor prognosis. Conclusions Taken together, our results indicate that SHCBP1 may promote the metastasis of SS by inducing EMT through targeting TGF-β1/Smad signaling pathway and can be a potential molecular target for SS therapy.

Breast cancer has the characteristics of high metastasis and recurrence and ranks first in incidence and mortality among female malignant tumors. Shc SH2-domain binding protein 1 (SHCBP1) is an important protein in intracellular signal transduction and cell division, but the role of SHCBP1 in breast cancers remains elusive. Here, we found that SHCBP1 deficiency inhibited the proliferation of breast cancer cells. Mechanistically, SHCPB1 significantly downregulates the mRNA level of CXCL2, which in turn activates the AKT and ERK signaling, while inactivates the p21 and p27 signaling. In addition, overexpression of SHCPB1 downregulates the protein levels of p21 and p27, which could be completely reversed by restoration of CXCL2 expression. Moreover, we analyzed the expression of both SHCPB1 and CXCL2, and found that SHCPB1 is highly expressed in breast cancer cells or tissues from breast cancer patients compared to normal breast cells or adjacent normal tissues, while CXCL2 is lowly expressed in breast cancer cells or tissues. Collectively, our study reveals that SHCBP1 plays an oncogenic role in breast cancer tumorigenesis partially through inhibiting the inflammatory response and ultimately activating the proliferation of breast cancers., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The incidence of cancer is increasing globally, and it is the most common cause of death. The identification of novel cancer diagnostic and prognostic biomarkers is important for developing cancer treatment strategies and reducing mortality. SHCSH2 domain-binding protein 1 (SHCBP1) is a protein that specifically binds to the SH2 domain of Src homology–collagen. It participates in the regulation of a variety of signal transduction pathways and can activate a variety of signaling molecules to perform a series of physiological functions. SHCBP1 is expressed in a variety of human tissues, but its abnormal expression in various systems is associated with cancer. SHCBP1 is abnormally expressed in a variety of tumors, and plays roles in almost all aspects of cancer biology (such as cell proliferation, apoptosis prevention, invasion, and metastasis) through various possible mechanisms. Its expression level is related to the clinicopathological characteristics of patients. In addition, the SHCBP1 expression pattern is closely related to cancer type, stage, and other clinical variables. Therefore, SHCBP1 is a promising tumor biomarker for cancer diagnosis and prognosis and a potential therapeutic target. This article reviews the expression, biological functions, mechanisms, and potential clinical significance of SHCBP1 in various human tumors to provide a new theoretical basis for clinical molecular diagnosis, molecular targeted therapy, and scientific research on cancer. [Display omitted] • SHCBP1 is dysregulated in a variety of human cancers. • According to the classification of disease, mechanism and prognosis, the role of SHCBP1 on cancer field was summarized. • SHCBP1 is a potential human cancer biomarker that shows great potential for cancer diagnosis, prognosis, and treatment. • This review provides a new theoretical basis for clinical molecular diagnosis, molecular targeted therapy and scientific research of cancer. [ABSTRACT FROM AUTHOR]

Background: Previous studies have revealed the significant roles of SHC SH2 domain-binding protein 1 (SHCBP1) in occurrence and progression of cancers, but there is no pan-cancer analysis of SHCBP1., Methods: In this study, we explored the potential carcinogenic role of SHCBP1 across 33 tumors from the TCGA and GTEx databases. We investigated SHCBP1 expression, prognosis, genetic alterations, tumor mutational burden (TMB) score, microsatellite instability (MSI) and tumor microenvironment from TIMER2, GEPIA2, UALCAN and cBioPortal databases. Moreover, the cellular functions and potential mechanisms were evaluated by GO and KEGG analysis. Besides, the mRNA expression of SHCBP1 was examined using qRT-PCR assay in gastrointestinal cancers., Results: SHCBP1 was significantly upregulated in various cancers, and apparent relationship existed between SHCBP1 and survival prognosis in patients. The TMB, MSI, and tumor microenvironment analysis indicated that SHCBP1 was closely related to immune checkpoints, immune targets, as well as CD4+ naive T cell, CD8+ T cell, and neutrophil. Moreover, the cellular functions of SHCBP1 were mainly in regulating cell cycle motor protein activity. In addition, we validated that SHCBP1 mRNA expression was over-expressed in gastrointestinal cancers., Conclusions: This study was the first to systematically determine the prognostic value of SHCBP1, providing a forward-looking perspective on immunotherapy and cellular processes in pan-cancer.

Background SHC SH2-binding protein 1, a member of Src homolog and collagen homolog (Shc) family, has been recently identified in different contexts in unbiased screening assays. It has been reported to be over-expressed in several malignant cancers. Methods Immunohistochemistry of SHCBP1 on 128 breast cancer tissues and adjacent normal tissues were used to evaluate the prognostic significance of SHCBP1. Survival analyses were performed by Kaplan–Meier method. CRISPR/CAS9 method was used to knockout SHCBP1 expression. CRISPR/CAS9 technology was used to knockout SHCBP1 in 2 breast cancer cell lines. MTT assay, BrdU assay, colony formation assay, cell cycle assay and apoptosis analysis in MCF-7 and MDA-MB-231 cell lines were carried out to evaluate the effects of SHCBP1 on breast cancer in vitro. Results Immunohistochemical analysis revealed SHCBP1 was significantly up-regulated in breast cancer tissues compared with adjacent normal tissues (82 of 128, 64%). Over-expressed SHCBP1 was correlated with advanced clinical stage and poorer survival. Ablation of SHCBP1 inhibited the proliferation in vitro. SHCBP1 knockout increased cyclin-dependent kinase inhibitor p21, and decreased the Cyclin B1 and CDK1. Conclusion Our study suggests SHCBP1 is dysregulated expressed in breast cancer and plays a critical role in cancer progression, which can be a potential prognosis predictor of breast cancer. [ABSTRACT FROM AUTHOR]

Objective: Shc SH2 domain-binding protein (SHCBP1) is involved in regulating tumour progression in a variety of tumour types. The aim of this study was to analyze the prognostic landscape of SHCBP1 in pan-cancer and investigate the relationship between SHCBP1 expression and tumour immune microenvironment., Methods: The Cancer Genome Atlas (TCGA) and genotype tissue expression (GTEx) database were used for obtaining the required data for the evaluation of SHCBP1 expression. The clinical characteristics and prognostic role of SHCBP1 were analyzed by using TCGA cohort. This was followed by gene set enrichment analysis by R software. Based on TCGA pan-cancer data, the correlation between SHCBP1 expression and immune infiltration, immune-related genes, microsatellite instability (MSI), and tumour mutational burden (TMB) was discussed. Finally, the half-maximum inhibitory concentration (IC 50 ) values of 192 anti-cancer drugs were obtained from the Genomics of Drug Sensitivity in Cancer (GDSC) database and their correlation with SHCBP1 was analyzed., Results: SHCBP1 was upregulated in most tumours showing a significant association with poor prognosis. Gene set enrichment analysis revealed SHCBP1 relation to the immunity, cell cycle, and cancer pathway in various types of tumour. SHCBP1 expression also showed a positive correlation with tumour-associated macrophages (TAMs) and immunosuppressive genes including TGFBR1, PD-L1 and TGFB1 and so on. In addition, high expression of SHCBP1 in patients was associated with resistance to a variety of anti-tumour drugs., Conclusion: The present study confirms SHCBP1 as a poor prognostic marker of cancers. Its high expression is suggested to be involved in immunological resistance to a variety of anti-tumour drugs., (© 2022 by the Association of Clinical Scientists, Inc.)

Centralspindlin, which is composed of MgcRacGAP and MKLP1, is essential for central spindle formation and cytokinetic furrow ingression. MgcRacGAP utilizes its GAP domain to inactivate Rac1 and induce furrow ingression in mammalian cells. In this report, we present a novel regulatory mechanism for furrowing that is mediated by the phosphorylation of SHC SH2-domain binding protein 1 (SHCBP1), a binding partner of centralspindlin, by Aurora B (AurB). AurB phosphorylates Ser634 of SHCBP1 during mitosis. We generated a phosphorylation site mutant, S634A-SHCBP1, which was prematurely recruited to the central spindle during anaphase and inhibited furrowing. An in vitro GAP assay demonstrated that SHCBP1 can suppress the MgcRacGAP-mediated inactivation of Rac1. In addition, the inhibition of Rac1 activity rescued the furrowing defect induced by S634A-SHCBP1 expression. Thus, AurB phosphorylates SHCBP1 to prevent the premature localization of SHCBP1 to the central spindle and ensures that MgcRacGAP inactivates Rac1 to promote the ingression of the cytokinetic furrow. [ABSTRACT FROM AUTHOR]

Shc SH2-domain binding protein 1 (SHCBP1), a protein specific binding to SH2 domain of Src homolog and collagen homolog (Shc), takes part in the regulation of various signal transduction pathways, which has been reported to be associated with tumorigenesis and progression. However, the pathological mechanisms are not completely investigated. Thus, this study aimed to comprehensively elucidate the potential functions of SHCBP1 in multiple cancer types. The comprehensive analyses for SHCBP1 in various tumors, including gene expression, diagnosis, prognosis, immune-related features, genetic alteration, and function enrichment, were conducted based on multiple databases and analysis tools. SHCBP1 was upregulated in most types of cancers. The results of qRT-PCR had confirmed that SHCBP1 mRNA was significantly upregulated in lung adenocarcinoma (LUAD) and liver hepatocellular carcinoma (LIHC) cell lines. Based on the receiver operating characteristic (ROC) and survival analysis, SHCBP1 was considered as a potential diagnostic and prognostic biomarker. Furthermore, SHCBP1 expression was linked with tumor immunity and immunosuppressive microenvironment according to the correlation analysis of SHCBP1 expression with immune cells infiltration, immune checkpoint genes, and immune-related genes (MHC genes, chemokines, and chemokines receptors). Moreover, SHCBP1 expression correlated with tumor mutational burden (TMB), microsatellite instability (MSI), and neoantigens. The feature of SHCBP1 mutational landscape in pan-cancer was identified. Finally, we focused on investigating the clinical significance and the potential biological role of SHCBP1 in LUAD. Our study comprehensively uncovered that SHCBP1 could be identified as an immune-related biomarker for cancer diagnosis and prognosis, and a potential therapeutic target for tumor immunotherapy., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

• Oroxylin A suppressed DMBA/TPA-induced skin tumorigenesis in mice. • Oroxylin A inhibited the DMBA/TPA-induced inflammation in skin tumor and serum of mice. • Oroxylin A inhibited TPA-induced cell transformation and inflammation of JB6 P + cells. • Oroxylin A inhibited the expression of SHCBP1 in vivo and in vitro. • Overexpression of SHCBP1 attenuated the anti-inflammatory effect of oroxylin A in vitro. Accumulating evidence has shown that SHC SH2 domain-binding protein 1 (SHCBP1) functions as an oncogene and participated in the progression of various cancers. Oroxylin A, an active ingredient extracted from Chinese Medicine Scutellaria baicalensis , shows strong anticancer effects on multiple cancers, however, the pharmacological effect of oroxylin A on skin cancer and the regulatory effect of SHCBP1 on this process have never been evaluated. The present study was aimed at elucidating the effect of oroxylin A on carcinogen (DMBA/TPA)-induced skin tumorigenesis, and to further clarify the role of SHCBP1 in oroxylin A induced antitumor effect. Pretreatment with oroxylin A remarkably inhibited DMBA/TPA-induced tumor formation and growth, and significantly reduced tumor incidence and the average number of tumors per mouse. Oroxylin A suppressed DMBA/TPA-induced skin hyperplasia and tumor proliferation. Oroxylin A significantly inhibited the expression of several inflammatory factors in vivo. In vitro experiments found that oroxylin A inhibited TPA-induced cell malignant transformation of skin epidermal JB6 P + cells. Besides, oroxylin A significantly suppressed the levels of TPA-induced inflammatory factors in vitro. Mechanistic studies showed that oroxylin A remarkably inhibited TPA-induced increased expression of SHCBP1. Overexpression of SHCBP1 attenuated the oroxylin A-induced anti-inflammatory effect. In addition, TPA increased the expression of nuclear NF-κB p65, and SHCBP1 siRNA notably decreased the nuclear NF-κB p65 expression in JB6 P + cells. Collectively, the anti-skin cancer effect of oroxylin A may possibly by inhibiting inflammation via suppression of SHCBP1. Oroxylin A might be a potential candidate compound for the treatment of skin cancer. [ABSTRACT FROM AUTHOR]

FGF13, a member of the FGF subfamily, has been found to be highly expressed in cancer cells such as prostate cancer, melanoma, glioma and multiple myeloma. However, the mechanism of FGF13 function during cancer cell proliferation remains to be unexplored, especially Non-small cell lung cancer (NSCLC). In this study, the cell proliferation effect of FGF13 on A549 cells was checked by CCK-8, clone formation, Ki67 immunofluorescence staining and Flow Cytometry assay. Localization of FGF13 within A549 cells was performed with confocal laser scanning microscope. The protein variations and interaction were measured by western blotting and co-immunoprecipitation analysis. It showed that FGF13 was mainly distributed in the cytoplasm and exhibited a high expression level in A549 cells. High expression of FGF13 activated AKT-GSK3 signaling pathway, and inhibited the activity of p21 and p27. Thus, FGF13 enhanced the process of transition from G1 to S phase and promoted A549 cells proliferation. Furthermore, the interaction between FGF13 and SHCBP1 was confirmed. Meanwhile, FGF13 and SHCBP1 had a cooperative effect to accelerate the cell cycle progression, especially the ability to promote cell proliferation is significantly enhanced via protein interaction. Hence, we conclude that FGF13 played a positive regulation role during A549 cells proliferation. FGF13 interacted with SHCBP1 to facilitate cell cycle progression, providing new insights into deep understanding of non-small cell lung cancer mechanisms of proliferation and regulation function of FGF13.

A challenge in developing novel strategies for penile cancer (PC) is the limited understanding of the regulatory mechanisms involved in PC development. This study aims to examine the expression of SHC SH2 Domain-Binding Protein 1 (SHCBP1) in PC and to explore its oncogenic function. Aberrant SHCBP1 expression was observed in PC tissues compared with normal penile tissues. SHCBP1 expression was significantly associated with the pathological grade, T stage, nodal status, and pelvic lymph node metastasis, and could serve as an independent factor for unfavorable overall survival in PC. Manipulation of SHCBP1 expression affected cell proliferation, soft agar clonogenesis, and cell migration and invasion in PC cell lines. Moreover, we identified STAT3/c-Myc signaling as a potential downstream target of SHCBP1. SHCBP1 interacted with JAK2 and STAT3 upon EGF stimulation, which might regulate STAT3/c-Myc signaling activation in PC cells. Disruption of STAT3/c-Myc signaling attenuated cell proliferation and cell migration/invasion in PC cell lines. Nevertheless, overexpression of constitutively activated STAT3 or c-Myc rescued cell proliferation and cell migration/invasion caused by SHCBP1 depletion in PC cell lines. Consistently, SHCBP1 depletion attenuated STAT3/c-Myc signaling and suppressed tumor growth in a murine xenograft model. Importantly, correlated expression of SHCBP1, p-STAT3, and c-Myc was observed in PC tissues, confirming the clinical relevance of SHCBP1/STAT3/c-Myc signaling in PC. In conclusion, aberrant SHCBP1 expression could serve as a potential prognostic biomarker for PC. SHCBP1 might activate the STAT3/c-Myc signaling pathway to promote tumor progression in PC, which may serve as a potential target for PC treatment., Competing Interests: None., (AJCR Copyright © 2020.)

Lung cancer is the leading cause for cancer death due to refractory nature to current treatment strategies, understanding the regulatory mechanism of therapy resistance of lung cancer is important for lung cancer therapy. Here, we aimed to study the role of SHCBP1 in lung cancer cisplatin resistance, we found SHCBP1 was upregulated in lung cancer tissues and cells, patients with high SHCBP1 had poor prognosis. SHC binding and spindle associated 1 (SHCBP1) overexpression promoted cisplatin induced apoptosis resistance, migration and invasion determined by apoptosis assay and transwell assay with or without Matrigel, while SHCBP1 knockdown inhibited cisplatin induced apoptosis resistance, migration and invasion. Wnt pathway promoted lung cancer progression, we found SHCBP1 activated Wnt pathway, characterized by promoting β-catenin nuclear translocation. Inhibition of Wnt pathway in SHCBP1 overexpression cells reversed the effect of SHCBP1 overexpression, confirming SHCBP1 promoted lung cancer progression through activating Wnt pathway. We also found SHCBP1 expression was positively corrected with Wnt pathway activity in lung cancer samples. In summary, we found SHCBP1 promoted cisplatin induced apoptosis resistance, migration and invasion through activating Wnt pathway, providing a potential target for lung cancer therapy. [ABSTRACT FROM AUTHOR]

Src homolog and collagen homolog (Shc) proteins have been identified as adapter proteins associated with cell surface receptors and have been shown to play important roles in signaling and disease. Shcbp1 acts as a Shc SH2-domain binding protein 1 and is involved in the regulation of signaling pathways, such as FGF, NF-κB, MAPK/ERK, PI3K/AKT, TGF-β1/Smad and β -catenin signaling. Shcbp1 participates in T cell development, the regulation of downstream signal transduction pathways, and cytokinesis during mitosis and meiosis. In addition, Shcbp1 has been demonstrated to correlate with Burkitt-like lymphoma, breast cancer, lung cancer, gliomas, synovial sarcoma, human hepatocellular carcinoma and other diseases. Shcbp1 may play an important role in tumorigenesis and progression. Accordingly, recent studies are reviewed herein to discuss and interpret the role of Shcbp1 in normal cell proliferation and differentiation, tumorigenesis and progression, as well as its interactions with proteins., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Gliomas are common, aggressive central nervous system tumors with poor overall survival rates. Despite improvements in neurosurgery, chemotherapy, and radiotherapy, the outcomes of patients with malignant gliomas remain poor. Therefore, increased knowledge of the molecular mechanisms that regulate glioma progression is crucial to identify novel therapeutic targets. Here, we reported that SHCBP1, a member of Src homolog and collagen homolog (Shc) family, was significantly overexpressed in glioma tissues and glioma cell lines compared to the corresponding normal tissues and cells. Ectopic overexpression of SHCBP1 promoted glioma cell migration and invasion, whereas knockdown of endogenous SHCBP1 had the opposite effects. Importantly, we demonstrated that SHCBP1 promoted aggressiveness in gliomas by activating the NF-κB signaling pathway. Collectively, our study indicates that SHCBP1 plays a pivotal role to promote progression in gliomas and targeting the oncogenic effects of SHCBP1 may provide a clinical strategy to treat gliomas., (© 2018 Wiley Periodicals, Inc.)

Background: Our previous studies reported that SHC SH2-domain binding protein 1 (SHCBP1) functions as an oncogene via promoting cell proliferations in synovial sarcoma (SS) cells. However, whether SHCBP1 has any effect on tumor metastasis remains unexplored., Methods: The expression of SHCBP1 was analyzed in 76 SS tissues and two SS cell lines by immunohistochemistry and real-time RT-PCR. The relationship between SHCBP1 expression and the clinicopathological features of SS was investigated. The role of SHCBP1 in SS cell adhesion, migration, invasion and angiogenesis was explored by adhesion, Wound healing, Transwell, and Matrigel tube formation assays. Western blotting was conducted to detect the protein expressions of TGF-β1/Smad signaling pathway and EMT-related markers. The key molecules associated with migration, invasion and EMT were evaluated by immunohistochemistry in tumor specimens., Results: In current study, we demonstrated that SHCBP1 overexpression significantly enhanced adhesion, migration, invasion and angiogenesis of SS cells. In contrast, SHCBP1 knockdown elicited the opposite effects on these phenotypes in vitro. SHCBP1 promoted tumor metastasis through inducing epithelial-mesenchymal transition (EMT) in SS cells. SHCBP1 knockdown could block the incidence of metastasis and EMT in SS cells. Furthermore, transforming growth factor-β1 (TGF-β1) induced SHCBP1 expression in a time-dependent pattern and SHCBP1 knockdown inhibited TGF-β1-induced EMT. The activation of the TGF-β1/Smad signaling pathway was involved in the oncogenic functions of SHCBP1 in SS. In addition, high expression of SHCBP1 in SS patients was associated with tumor progression and decreased survival as well as poor prognosis., Conclusions: Taken together, our results indicate that SHCBP1 may promote the metastasis of SS by inducing EMT through targeting TGF-β1/Smad signaling pathway and can be a potential molecular target for SS therapy.

The SS18-SSX1 fusion gene has been shown to play important roles in the development of synovial sarcoma (SS), but the underlying molecular mechanisms and its downstream target genes are still not clear. Here SHC SH2-domain binding protein 1 (SHCBP1) was identified and validated to be a novel downstream target gene of SS18-SSX1 by using microarray assay, quantitative real-time (qPCR) and western blot. Expression of SHCBP1 was firstly confirmed in SS cell line and SS tissues. The effects of SHCBP1 overexpression or knockdown on SS cell proliferation and tumorigenicity were then studied by cell proliferation, DNA replication, colony formation, flow cytometric assays, and its in vivo tumorigenesis was determined in the nude mice. Meanwhile, the related signaling pathways of SHCBP1 were also examined in SS cells. The results indicated that SHCBP1 was significantly increased in SS cells and SS tissues compared with adjacent noncancerous tissues. The expression of SHCBP1 was demonstrated to be positively correlated with the SS18-SSX1 level. Overexpression and ablation of SHCBP1 promoted and inhibited, respectively, the proliferation and tumorigenicity of SS cells in vitro. SHCBP1 knockdown also significantly inhibited SS cell growth in nude mice, and lowered the MAPK/ERK and PI3K/AKT/mTOR signaling pathways and cyclin D1 expression. Our findings disclose that SHCBP1 is a novel downstream target gene of SS18-SSX1, and demonstrate that the oncogene SS18-SSX1 promotes tumorigenesis by increasing the expression of SHCBP1, which normally acts as a tumor promoting factor.

How self-renewal versus differentiation of neural progenitor cells is temporally controlled during early development remains ill-defined. We show that mouse Lin41 (mLin41) is highly expressed in neural progenitor cells and its expression declines during neural differentiation. Loss of mLin41 function in mice causes reduced proliferation and premature differentiation of embryonic neural progenitor cells. mLin41 was recently implicated as the E3 ubiquitin ligase that mediates degradation of Argonaute 2 (AGO2), a key effector of the microRNA pathway. However, our mechanistic studies of neural progenitor cells indicate mLin41 is not required for AGO2 ubiquitination or stability. Instead, mLin41-deficient neural progenitors exhibit hyposensitivity for fibroblast growth factor (FGF) signaling. We show that mLin41 promotes FGF signaling by directly binding to and enhancing the stability of Shc SH2-binding protein 1 (SHCBP1) and that SHCBP1 is an important component of FGF signaling in neural progenitor cells. Thus, mLin41 acts as a temporal regulator to promote neural progenitor cell maintenance, not via the regulation of AGO2 stability, but through FGF signaling. [ABSTRACT FROM AUTHOR]

The centralspindlin complex, which is composed of MKLP1 and MgcRacGAP, is one of the crucial factors involved in cytokinesis initiation. Centralspindlin is localized at the middle of the central spindle during anaphase and then concentrates at the midbody to control abscission. A number of proteins that associate with centralspindlin have been identified. These associating factors regulate furrowing and abscission in coordination with centralspindlin. A recent study identified a novel centralspindlin partner, called Nessun Dorma, which is essential for germ cell cytokinesis in Drosophila melanogaster. SHCBP1 is a human ortholog of Nessun Dorma that associates with human centralspindlin. In this report, we analyzed the interaction of SHCBP1 with centralspindlin in detail and determined the regions that are required for the interaction. In addition, we demonstrate that the central region is necessary for the SHCBP1 dimerization. Both MgcRacGAP and MKLP1 are degraded once cells exit mitosis. Similarly, endogenous and exogenous SHCBP1 were degraded with mitosis progression. Interestingly, SHCBP1 expression was significantly reduced in the absence of centralspindlin, whereas centralspindlin expression was not affected by SHCBP1 knockdown. Finally, we demonstrate that SHCBP1 depletion promotes midbody structure disruption and inhibits abscission, a final stage of cytokinesis. Our study gives novel insight into the role of SHCBP in cytokinesis completion.