The dynamic role of nucleoprotein SHCBP1 in the cancer cell cycle and its potential as a synergistic target for DNA-damaging agents in cancer therapy.

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.

p66ShcA promotes malignant breast cancer phenotypes by alleviating energetic and oxidative stress.

Significant efforts have focused on identifying targetable genetic drivers that support the growth of solid tumors and/or increase metastatic ability. During tumor development and progression to metastatic disease, physiological and pharmacological selective pressures influence parallel adaptive strategies within cancer cell sub-populations. Such adaptations allow cancer cells to withstand these stressful microenvironments. This Darwinian model of stress adaptation often prevents durable clinical responses and influences the emergence of aggressive cancers with increased metastatic fitness. However, the mechanisms contributing to such adaptive stress responses are poorly understood. We now demonstrate that the p66ShcA redox protein, itself a ROS inducer, is essential for survival in response to physiological stressors, including anchorage independence and nutrient deprivation, in the context of poor outcome breast cancers. Mechanistically, we show that p66ShcA promotes both glucose and glutamine metabolic reprogramming in breast cancer cells, to increase their capacity to engage catabolic metabolism and support glutathione synthesis. In doing so, chronic p66ShcA exposure contributes to adaptive stress responses, providing breast cancer cells with sufficient ATP and redox balance needed to withstand such transient stressed states. Our studies demonstrate that p66ShcA functionally contributes to the maintenance of aggressive phenotypes and the emergence of metastatic disease by forcing breast tumors to adapt to chronic and moderately elevated levels of oxidative stress.

SHC4 orchestrates ß-catenin pathway-mediated metastasis in triple-negative breast cancer by promoting Src kinase autophosphorylation.

Triple-negative breast cancer (TNBC) is highly aggressive and metastatic, and has the poorest prognosis among all breast cancer subtypes. Activated ß-catenin is enriched in TNBC and involved in Wnt signaling-independent metastasis. However, the underlying mechanisms of ß-catenin activation in TNBC remain unknown. Here, we found that SHC4 was upregulated in TNBC and high SHC4 expression was significantly correlated with poor outcomes. Overexpression of SHC4 promoted TNBC aggressiveness in vitro and facilitated TNBC metastasis in vivo. Mechanistically, SHC4 interacted with Src and maintained its autophosphorylated activation, which activated ß-catenin independent of Wnt signaling, and finally upregulated the transcription and expression of its downstream genes CD44 and MMP7. Furthermore, we determined that the PxPPxPxxxPxxP sequence on CH2 domain of SHC4 was critical for SHC4-Src binding and Src kinase activation. Overall, our results revealed the mechanism of ß-catenin activation independent of Wnt signaling in TNBC, which was driven by SHC4-induced Src autophosphorylation, suggesting that SHC4 might be a potential prognostic marker and therapeutic target in TNBC.

Therapeutic potential of SHCBP1 inhibitor AZD5582 in pancreatic cancer treatment.

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.

[Study of senescence protein p66Shc on myocardial tissue repair in adult mice].

Our previous study has shown that p66Shc plays an important role in the process of myocardial regeneration in newborn mice, and p66Shc deficiency leads to weakened myocardial regeneration in newborn mice. This study aims to explore the role of p66Shc protein in myocardial injury repair after myocardial infarction in adult mice, in order to provide a new target for the treatment of myocardial injury after myocardial infarction. Mouse myocardial infarction models of adult wild-type (WT) and p66Shc knockout (KO) were constructed by anterior descending branch ligation. The survival rate and heart-to-body weight ratio of two models were compared and analyzed. Masson's staining was used to identify scar area of injured myocardial tissue, and myocyte area was determined by wheat germ agglutinin (WGA) staining. TUNEL staining was used to detect the cardiomyocyte apoptosis. The protein expression of brain natriuretic peptide (BNP), a common marker of myocardial hypertrophy, was detected by Western blotting. The results showed that there was no significant difference in survival rate, myocardial scar area, myocyte apoptosis, and heart weight to body weight ratio between the WT and p66ShcKO mice after myocardial infarction surgery. Whereas the protein expression level of BNP in the p66ShcKO mice was significantly down-regulated compared with that in the WT mice. These results suggest that, unlike in neonatal mice, the deletion of p66Shc has no significant effect on myocardial injury repair after myocardial infarction in adult mice.

The function and immune role of cuproptosis associated hub gene in Barrett's esophagus and esophageal adenocarcinoma.

Barrett's esophagus (BE) is a precancerous lesion of esophageal adenocarcinoma (EAC), with approximately 3-5% of patients developing EAC. Cuproptosis is a kind of programmed cell death phenomenon discovered in recent years, which is related to the occurrence and development of many diseases. However, its role in BE and EAC is not fully understood. We used single sample Gene Set Enrichment Analysis (ssGSEA) for differential analysis of BE in the database, followed by enrichment analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO) and GSEA, Protein-Protein Interaction (PPI), Weighted Gene Co-expression Network Analysis (WGCNA), Receiver Operating Characteristic Curve (ROC) and finally Quantitative Real Time Polymerase Chain Reaction (qRT-PCR) and immunohistochemistry (IHC) of clinical tissues. Two hub genes can be obtained by intersection of the results obtained from the cuproptosis signal analysis based on BE. The ROC curves of these two genes predicted EAC, and the Area Under the Curve (AUC) values could reach 0.950 and 0.946, respectively. The mRNA and protein levels of Centrosome associated protein E (CENPE) and Shc SH2 domain binding protein 1 (SHCBP1) were significantly increased in clinical EAC tissues. When they were grouped by protein expression levels, high expression of CENPE or SHCBP1 had a poor prognosis. The CENPE and SHCBP1 associated with cuproptosis may be a factor promoting the development of BE into EAC which associated with the regulation of NK cells and T cells.

Biological functions and therapeutic potential of SHCBP1 in human cancer.

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.

The longevity protein p66Shc is required for neonatal heart regeneration.

The longevity protein p66Shc is essential for the senescence signaling that is involved in heart regeneration and remodeling. However, the exact role of p66Shc in heart regeneration is unknown. In this study, we found that p66Shc deficiency decreased neonatal mouse cardiomyocyte (CM) proliferation and impeded neonatal heart regeneration after apical resection injury. RNA sequencing and functional verification demonstrated that p66Shc regulated CM proliferation by activating ß-catenin signaling. These findings reveal the critical role of p66Shc in neonatal heart regeneration and provide new insights into senescence signaling in heart regeneration.

Identification and characterization of sex-dependent gene expression profile in glioblastoma.

Glioblastoma (GBM) is the most lethal primary tumor in the human brain and lacks favorable treatment options. Sex differences in the outcome of GBM are broadly acknowledged, but the underlying molecular mechanisms remain largely unknown. To identify the sex-dependent critical genes in the progression of GBM, raw data from several microarray datasets with the same array platform were downloaded from the Gene Expression Omnibus (GEO) database. These datasets included tumorous and normal tissue from patients with GBM and crucial sex features. Then, the differentially expressed genes (DEGs) in female and male tumors were identified via bioinformatics analysis, respectively. Functional signatures of the identified DEGs were further annotated by Gene Ontology (GO) and pathway enrichment analyses. Venn diagram and functional protein-protein interaction (PPI) network analyses were performed to screen out the sex-specific DEGs. Survival analysis of patients with differences in the expression level of selected genes was then carried out using the data from The Cancer Genome Atlas (TCGA). Here, we showed that ECT2, AURKA, TYMS, CDK1, NCAPH, CENPU, OIP5, KIF14, ASPM, FBXO5, SGOL2, CASC5, SHCBP1, FN1, LOX, IGFBP3, CSPG4, and CD44 were enriched in female tumor samples, whereas TNFSF13B, CXCL10, CXCL8, CXCR4, TLR2, CCL2, and FCGR2A were enriched in male tumor samples. Among these key genes, interestingly, ECT2 was associated with increased an survival rate for female patients, whileTNFSF13B could be regarded as a potential marker of poor prognosis in male patients. These results suggested that sex differences in patients may be attributed to the heterogeneous gene activity, which might influence the oncogenesis and the outcomes of GBM.

Identification of Immune Infiltration and Prognostic Biomarkers in Small Cell Lung Cancer Based on Bioinformatic Methods from 3 Studies.

AIMS: This study aimed to investigate the correlation between gene expression and immune cell infiltration and the overall survival rate in tumor tissues, which may contribute to the therapy and prognosis of small cell lung cancer (SCLC) patients. BACKGROUND: SCLC is the most aggressive type of lung neoplasm. There is no proper marker for the treatment and prediction of prognosis in SCLC. OBJECTIVES: Three gene expression profiles of SCLC patients were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified between normal lung samples and SCLC lung samples. METHODS: Functional enrichment analysis of all DEGs was performed to explore the linkage among DEGs, the tumor immune microenvironment, and SCLC tumorigenesis. The common genes among the 3 groups in the Venn diagram and hub genes in protein-protein interaction (PPI) networks were considered potential key genes in SCLC patients. The TIMER (tumor immune estimation resource) database calculation and Kaplan-Meier survival curves were used to investigate the association between potential key genes and immune infiltrate prognosis of SCLC patients. RESULTS: A total of 750 (top 250 from each study) differentially expressed genes (DEGs) were identified. CLDN18 and BRIP1 were significantly related to immune infiltration in the tumor microenvironment. SHCBP1 and KIF23 were related mostly to prognosis in SCLC patients. CONCLUSION: The present study may provide some potential biomarkers for the therapy and prognosis of SCLC.

Mitochondrial Translocation of P66Shc Aggravates Cisplatin-induced AKI by Promoting Ferroptosis.

OBJECTIVE: The objective of this study is to evaluate the regulatory mechanism between P66Shc and ferroptosis in cisplatin-induced acute kidney injury (CP-AKI). METHODS: A CP-AKI model was constructed both in vivo and in vitro using C57BL/6 mice and HK-2 cells, respectively. Renal histopathological injury, reactive oxygen species (ROS), and apoptosis were detected. Some parameters of ferroptosis (e.g. 4HNE and GPX4) and the expression of P66Shc/ P-P66Shc both in mitochondria and cytoplasm were tested. In in vitro studies, HK-2 cells were incubated with CP (50 uM); additionally, Fer1 and P66Shc siRNA were applied to explore the molecular regulatory mechanism of P66Shc in ferroptosis. The levels of mitochondrial ROS, apoptosis and the expression of 4HNE,GPX4, P66Shc, and P-P66Shc were tested. Furthermore, the mitochondrial translocation of P66Shc was detected. RESULTS: CP treatment caused elevation of Scr, BUN and renal MDA levels and decreased renal SOD, GSH-PX and GPX4 levels. CP enhanced the expression of 4HNE, P66Shc and P-P66Shc both in vivo and in vitro. Renal oxidative stress and apoptosis were significantly increased in CP-AKI mice. Electron microscopy examination indicated obvious mitochondria injury in renal tubular cells of CP-AKI mice. The level of ferroptosis and the translocation of P-P66Shc from the cytoplasm to mitochondria were significantly increased in HK-2 cells under CP condition, and these effects were obviously blocked by P66Shc siRNA treatment. Conversely, pretreatment with the ferroptosis inhibitor (Fer1) had no effect on the expression and mitochondria translocation of PP66Shc under CP condition. CONCLUSION: Mitochondrial translocation of P66Shc could result in mitochondrial injury and lipid peroxide accumulation, which ultimately led to ferroptosis and aggravated CPinduced AKI.

Construction and Validation of a Prognostic Model Based on mRNAsi-Related Genes in Breast Cancer.

Background: Breast cancer is a big threat to the women across the world with substantial morbidity and mortality. The pressing matter of our study is to establish a prognostic gene model for breast cancer based on mRNAsi for predicting patient's prognostic survival. Methods: From The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, we downloaded the expression profiles of genes in breast cancer. On the basis of one-class logistic regression (OCLR) machine learning algorithm, mRNAsi of samples was calculated. Kaplan-Meier (K-M) and Kruskal-Wallis (K-W) tests were utilized for the assessment of the connection between mRNAsi and clinicopathological variables of the samples. As for the analysis on the correlation between mRNAsi and immune infiltration, ESTIMATE combined with Spearman test was employed. The weighted gene coexpression network analysis (WGCNA) network was established by utilizing the differentially expressed genes in breast cancer, and the target module with the most significant correlation with mRNAsi was screened. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to figure out the biological functions of the target module. As for the construction of the prognostic model, univariate, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analyses were performed on genes in the module. The single sample gene set enrichment analysis (ssGSEA) and tumor mutational burden were employed for the analysis on immune infiltration and gene mutations in the high- and low-risk groups. As for the analysis on whether this model had the prognostic value, the nomogram and calibration curves of risk scores and clinical characteristics were drawn. Results: Nine mRNAsi-related genes (CFB, MAL2, PSME2, MRPL13, HMGB3, DCTPP1, SHCBP1, SLC35A2, and EVA1B) comprised the prognostic model. According to the results of ssGSEA and gene mutation analysis, differences were shown in immune cell infiltration and gene mutation frequency between the high- and low-risk groups. Conclusion: Nine mRNAsi-related genes screened in our research can be considered as the biomarkers to predict breast cancer patients' prognoses, and this model has a potential relationship with individual somatic gene mutations and immune regulation. This study can offer new insight into the development of diagnostic and clinical treatment strategies for breast cancer.

Receptor-kinase EGFR-MAPK adaptor proteins mediate the epithelial response to Candida albicans via the cytolytic peptide toxin, candidalysin.

Candida albicans (C. albicans) is a dimorphic commensal human fungal pathogen that can cause severe oropharyngeal candidiasis (oral thrush) in susceptible hosts. During invasive infection, C. albicans hyphae invade oral epithelial cells (OECs) and secrete candidalysin, a pore-forming cytolytic peptide that is required for C. albicans pathogenesis at mucosal surfaces. Candidalysin is produced in the hyphal invasion pocket and triggers cell damage responses in OECs. Candidalysin also activates multiple MAPK-based signaling events that collectively drive the production of downstream inflammatory mediators that coordinate downstream innate and adaptive immune responses. The activities of candidalysin are dependent on signaling through the epidermal growth factor receptor (EGFR). Here, we interrogated known EGFR-MAPK signaling intermediates for their roles mediating the OEC response to C. albicans infection. Using RNA silencing and pharmacological inhibition, we identified five key adaptors, including growth factor receptor-bound protein 2 (Grb2), Grb2-associated binding protein 1 (Gab1), Src homology and collagen (Shc), SH2-containing protein tyrosine phosphatase-2 (Shp2), and casitas B-lineage lymphoma (c-Cbl). We determined that all of these signaling effectors were inducibly phosphorylated in response to C. albicans. These phosphorylation events occurred in a candidalysin-dependent manner and additionally required EGFR phosphorylation, matrix metalloproteinases (MMPs), and cellular calcium flux to activate a complete OEC response to fungal infection. Of these, Gab1, Grb2, and Shp2 were the dominant drivers of ERK1/2 activation and the subsequent production of downstream innate-acting cytokines. Together, these results identify the key adaptor proteins that drive the EGFR signaling mechanisms that underlie oral epithelial responses to C. albicans.

p66Shc in Cardiovascular Pathology.

p66Shc is a widely expressed protein that governs a variety of cardiovascular pathologies by generating, and exacerbating, pro-apoptotic ROS signals. Here, we review p66Shc's connections to reactive oxygen species, expression, localization, and discuss p66Shc signaling and mitochondrial functions. Emphasis is placed on recent p66Shc mitochondrial function discoveries including structure/function relationships, ROS identity and regulation, mechanistic insights, and how p66Shc-cyt c interactions can influence p66Shc mitochondrial function. Based on recent findings, a new p66Shc mitochondrial function model is also put forth wherein p66Shc acts as a rheostat that can promote or antagonize apoptosis. A discussion of how the revised p66Shc model fits previous findings in p66Shc-mediated cardiovascular pathology follows.

Gene expression profiling and in vitro functional studies reveal RAD54L as a potential therapeutic target in multiple myeloma.

BACKGROUND: Current advances in the molecular biology of multiple myeloma (MM) are not sufficient to fully delineate the genesis and development of this disease. OBJECTIVE: This study aimed to identify molecular targets underlying MM pathogenesis. METHODS: mRNA expression profiling for 29 samples (19 MM samples, 7 MM cell lines and 3 controls) were obtained using microarray. We evaluated the in vitro effects of RAD54L gene silencing on the proliferation, apoptosis and cell cycle distribution in KMS-28BM human MM cells using siRNA approach. Cell proliferation was determined by MTS assay while apoptosis and cell cycle distribution were analysed with flow cytometry. Gene and protein expression was evaluated using RT-qPCR and ELISA, respectively. RESULTS: Microarray results revealed a total of 5124 differentially expressed genes (DEGs), in which 2696 and 2428 genes were up-regulated and down-regulated in MM compared to the normal controls, respectively (fold change ≥ 2.0; P < 0.05). Up-regulated genes (RAD54L, DIAPH3, SHCBP1, SKA3 and ANLN) and down-regulated genes (HKDC1, RASGRF2, CYSLTR2) have never been reported in association with MM. Up-regulation of RAD54L was further verified by RT-qPCR (P < 0.001). In vitro functional studies revealed that RAD54L gene silencing significantly induced growth inhibition, apoptosis (small changes) and cell cycle arrest in G0/G1 phase in KMS-28BM (P < 0.05). Silencing of RAD54L also decreased its protein level (P < 0.05). CONCLUSIONS: This study has identified possible molecular targets underlying the pathogenesis of MM. For the first time, we reveal RAD54L as a potential therapeutic target in MM, possibly functioning in the cell cycle and checkpoint control.

p66Shc signaling does not contribute to tubular damage induced by renal ischemia-reperfusion injury in rat.

Renal ischemia-reperfusion (IR) injury is one of the major causes of acute kidney injury and represents a significant risk factor for renal transplantation. The level of renal damage is influenced by the ischemic duration and is caused by excessive amounts of produced reactive oxygen species (ROS). Adaptor protein p66Shc is known to regulate cellular and organ's sensitivity to oxidative stress and to contribute significantly to mitochondrial production of hydrogen peroxide in stress conditions. Studies carried out in cultured renal cells suggest that p66Shc-mediated mitochondrial dysfunction and ROS production are responsible for renal ischemic injury. We used our genetically modified rats, which either lack p66Shc expression, or express p66Shc variant, which constitutively generates increased quantities of hydrogen peroxide, to evaluate potential contribution of p66Shc signaling to renal damage in ischemia reperfusion rat model. Analysis of outer medulla tubule damage revealed the lack of contribution of either p66Shc expression or its constitutive signaling to IR injury in rat model.

Pro-oxidant vitamin C mechanistically exploits p66Shc/Rac1 GTPase pathway in inducing cytotoxicity.

P66Shc is the master regulator of oxidative stress whose pro-oxidant functioning is governed by ser36 phosphorylation. Phosphorylated p66Shc via Rac1 GTPase activation modulates ROS levels which in turn influence its pro-oxidative functions. Vitamin C at higher concentrations exhibits cytotoxic activity in various cancers, inducing ROS mediated cell death via pro-apoptotic mechanisms. Here we show a novel role of p66Shc in mediating pro-oxidant activity of vitamin C. Effect of vitamin C on the viability of breast cancer and normal cells was studied. High doses of vitamin C decreased viability of cancerous cells but not normal cells. Docking study displayed significant binding affinity of vitamin C with p66Shc PTB domain. Western blot results suggest that vitamin C not only enhances p66Shc expression but also induces its ser36 phosphorylation. Vitamin C at high doses was also found to activate Rac1, enhance ROS production and induce apoptosis. Interestingly, ser36 phosphorylation mutant transfection and pretreatment with antioxidant N-acetylcysteine results indicate that vitamin C induced Rac1 activation, ROS production and apoptosis is p66Shc ser36 phosphorylation dependent. Overall, results highlight that vitamin C mechanistically explores p66Shc/Rac1 pathway in inducing apoptosis and thus can pave a way to use this pathway as a potential therapeutic target in breast cancers.

EGF-induced nuclear translocation of SHCBP1 promotes bladder cancer progression through inhibiting RACGAP1-mediated RAC1 inactivation.

Bladder cancer is a highly heterogeneous and aggressive malignancy with a poor prognosis. EGF/EGFR activation causes the detachment of SHC-binding protein 1 (SHCBP1) from SHC adapter protein 1 (SHC1), which subsequently translocates into the nucleus and promotes cancer development via multiple signaling pathways. However, the role of the EGF-SHCBP1 axis in bladder cancer progression remains unexplored. Herein, we report that SHCBP1 is upregulated in bladder cancer tissues and cells, with cytoplasmic or nuclear localization. Released SHCBP1 responds to EGF stimulation by translocating into the nucleus following Ser273 phosphorylation. Depletion of SHCBP1 reduces EGF-induced cell migration and invasiveness of bladder cancer cells. Mechanistically, SHCBP1 binds to RACGAP1 via its N-terminal domain of amino acids 1 ~ 428, and this interaction is enhanced following EGF treatment. Furthermore, SHCBP1 facilitates cell migration by inhibiting RACGAP-mediated GTP-RAC1 inactivation, whose activity is indispensable for cell movement. Collectively, we demonstrate that the EGF-SHCBP1-RACGAP1-RAC1 axis acts as a novel regulatory mechanism of bladder cancer progression, which offers a new clinical therapeutic strategy to combat bladder cancer.

Functional roles of the SHCBP1 and KIF23 interaction in modulating the cell-cycle and cisplatin resistance of head and neck squamous cell carcinoma.

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/ß-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.

Shc inhibitor idebenone ameliorates liver injury and fibrosis in dietary NASH in mice.

Shc expression rises in human nonalcoholic steatohepatitis (NASH) livers, and Shc-deficient mice are protected from NASH-thus Shc inhibition could be a novel therapeutic strategy for NASH. Idebenone was recently identified as the first small-molecule Shc inhibitor drug. We tested idebenone in the fibrotic methionine-choline deficient (MCD) diet and the metabolic fast food diet (FFD) mouse models of NASH. In the fibrotic MCD NASH model, idebenone reduced Shc expression and phosphorylation in peripheral blood mononuclear cells and Shc expression in the liver; decreased serum alanine aminotransferase and aspartate aminotransferase; and attenuated liver fibrosis as observed by quantitative polymerase chain reaction (qPCR) and hydroxyproline quantification. In the metabolic FFD model, idebenone administration improved insulin resistance, and reduced inflammation and fibrosis shown with qPCR, hydroxyproline measurement, and histology. Thus, idebenone ameliorates NASH in two mouse models. As an approved drug with a benign safety profile, Idebenone could be a reasonable human NASH therapy.