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Circulation Research Jul 2020Doxorubicin is one of the most potent antitumor agents available; however, its clinical use is restricted because it poses a risk of severe cardiotoxicity. Previous work...
RATIONALE
Doxorubicin is one of the most potent antitumor agents available; however, its clinical use is restricted because it poses a risk of severe cardiotoxicity. Previous work has established that CircITCH (circular RNA ITCH [E3 ubiquitin-protein ligase]) is a broad-spectrum tumor-suppressive circular RNA and that its host gene, ITCH (E3 ubiquitin protein ligase), is involved in doxorubicin-induced cardiotoxicity (DOXIC). Whether CircITCH plays a role in DOXIC remains unknown.
OBJECTIVE
We aimed to dissect the role of CircITCH in DOXIC and further decipher its potential mechanisms.
METHODS AND RESULTS
Circular RNA sequencing was performed to screen the potentially involved circRNAs in DOXI pathogenesis. Quantitative polymerase chain reaction and RNA in situ hybridization revealed that CircITCH was downregulated in doxorubicin-treated human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as well as in the autopsy specimens from cancer patients who suffered from doxorubicin-induced cardiomyopathy. Cell death/viability assays, detection of cardiomyocyte necrosis markers, microelectrode array, and cardiomyocyte functional assays revealed that CircITCH ameliorated doxorubicin-induced cardiomyocyte injury and dysfunction. Detection of cellular/mitochondrial oxidative stress and DNA damage markers verified that CircITCH alleviated cellular/mitochondrial oxidative stress and DNA damage induced by doxorubicin. RNA pull-down assays, Ago2 immunoprecipitation and double fluorescent in situ hybridization identified miR-330-5p as a direct target of CircITCH. Moreover, CircITCH was found to function by acting as an endogenous sponge that sequestered miR-330-5p. Bioinformatic analysis, luciferase reporter assays, and quantitative polymerase chain reaction showed that SIRT6 (sirtuin 6), BIRC5 (baculoviral IAP repeat containing 5, Survivin), and ATP2A2 (ATPase sarcoplasmic/endoplasmic reticulum Ca transporting 2, SERCA2a [SR Ca-ATPase 2]) were direct targets of miR-330-5p and that they were regulated by the CircITCH/miR-330-5p axis in DOXIC. Further experiments demonstrated that CircITCH-mediated alleviation of DOXIC was dependent on the interactions between miR-330-5p and the 3'-UTRs of SIRT6, BIRC5, and ATP2A2 mRNA. Finally, AAV9 (adeno-associated virus serotype 9) vector-based overexpression of the well-conserved CircITCH partly prevented DOXIC in mice.
CONCLUSIONS
CircITCH represents a novel therapeutic target for DOXIC because it acts as a natural sponge of miR-330-5p, thereby upregulating SIRT6, Survivin and SERCA2a to alleviate doxorubicin-induced cardiomyocyte injury and dysfunction.
Topics: 3' Untranslated Regions; Adenoviruses, Human; Animals; Antibiotics, Antineoplastic; Argonaute Proteins; Binding Sites; Biomarkers; Cardiotoxicity; Cell Death; Cell Survival; DNA Damage; Down-Regulation; Doxorubicin; Gene Silencing; Genes, Tumor Suppressor; Humans; Immunoprecipitation; In Situ Hybridization, Fluorescence; Mice; MicroRNAs; Mitochondria, Heart; Mutation; Myocardial Contraction; Myocytes, Cardiac; Necrosis; Oxidative Stress; RNA, Circular; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sirtuins; Survivin; Ubiquitin-Protein Ligases; Up-Regulation
PubMed: 32392088
DOI: 10.1161/CIRCRESAHA.119.316061 -
Stem Cell Reviews and Reports Oct 2020Survivin is one of the rare proteins that is differentially expressed in normal and cancer cells and is directly or indirectly involved in numerous pathways required for... (Review)
Review
Survivin is one of the rare proteins that is differentially expressed in normal and cancer cells and is directly or indirectly involved in numerous pathways required for tumor maintenance. It is expressed in almost all cancers and its expression has been detected at early stages of cancer. These traits make survivin an exceptionally attractive target for cancer therapeutics. Even with these promising features to be an oncotherapeutic target, there has been limited success in the clinical trials targeting survivin. Only recently it has emerged that survivin was not being specifically targeted which could have resulted in the negative clinical outcome. Also, focus of research has now shifted from survivin expression in the overall heterogeneous tumor cell populations to survivin expression in cancer stem cells as these cells have proved to be the major drivers of tumors. Therefore, in this review we have analyzed the expression of survivin in normal and cancer cells with a particular focus on its expression in cancer stem cell compartment. We have discussed the major signaling pathways involved in regulation of survivin. We have explored the current development status of various types of interventions for inhibition of survivin. Furthermore, we have discussed the challenges involving the development of potent and specific survivin inhibitors for cancer therapeutics. Finally we have given insights for some of the promising future anticancer treatments.
Topics: Drug Development; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Neoplastic Stem Cells; Stem Cells; Survivin
PubMed: 32691369
DOI: 10.1007/s12015-020-09995-4 -
World Journal of Gastroenterology Nov 2021Circulating tumor cells (CTCs) and survivin are indicators for tumor stage and metastasis, as well as epitheliomesenchymal transition, in various cancers, including...
BACKGROUND
Circulating tumor cells (CTCs) and survivin are indicators for tumor stage and metastasis, as well as epitheliomesenchymal transition, in various cancers, including hepatocellular cancer (HCC).
AIM
To explore the potential of survivin-positive CTCs, specifically, as a marker for tumor progression in HCC patients.
METHODS
We examined the survivin expression pattern in CTCs obtained from 179 HCC patients, and investigated the effects of survivin silencing and overexpression on the proliferation and invasion of HCC cells. CTC count and survivin expression in patient samples were examined using RNA hybridization.
RESULTS
All 179 patients were positive for CTC markers, and 94.41% of the CTCs were positive for survivin. The CTC and survivin-positive CTC counts were significantly higher in the HCC patients than in the normal controls, and were significantly associated with tumor stage and degree of differentiation. Further, survivin overexpression was found to induce HepG2 cell proliferation, reduce apoptosis, and improve invasive ability.
CONCLUSION
Survivin shows upregulated expression (indicative of anti-apoptotic effects) in HCC. Thus, survivin-positive CTCs are promising as a predictor of HCC prognosis and metastasis, and their accurate measurement may be useful for the management of this cancer.
Topics: Biomarkers, Tumor; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Neoplastic Cells, Circulating; Prognosis; Survivin
PubMed: 34887648
DOI: 10.3748/wjg.v27.i43.7546 -
European Review For Medical and... Jun 2018To investigate the expressions of HIF-1α, surviving, and VEGF in patients with hepatocarcinoma as well as the correlation analysis among them.
OBJECTIVE
To investigate the expressions of HIF-1α, surviving, and VEGF in patients with hepatocarcinoma as well as the correlation analysis among them.
PATIENTS AND METHODS
65 patients, who were admitted to our hospital and diagnosed as hepatocarcinoma from January 2014 to October 2015, were selected as hepatocarcinoma group, while 50 healthy cases that do not have hepatocarcinoma were selected as normal control group. The expression levels of HIF-1α, surviving, and VEGF in hepatocarcinoma tissues of hepatocarcinoma group and normal liver tissues of control group were detected by immunohistochemical (SP) staining method; then, the correlation among them was explored. The expression levels of HIF-1α, surviving, and VEGF protein in hepatocarcinoma tissues and corresponding normal tissues were detected by Western blot.
RESULTS
The positive expression rate of HIF-1α, surviving, and VEGF in hepatocarcinoma tissues of hepatocarcinoma group was respectively 46.2%, 55.4%, and 61.5%, significantly higher than that in cancer adjacent normal liver tissues of control group which was 2%, 2%, and 2%, and the differences were statistically significant (p<0.05). The expressions of HIF-1α, surviving, and VEGF in hepatocarcinoma tissues of patients with hepatocarcinoma were correlated with clinical stage, tumor differentiation degree and extrahepatic metastasis (p<0.05), but were not related to gender and tumor size (p>0.05). By Spearman rank correlation analysis, it could be seen that HIF-1α expression was positively correlated with VEGF protein expression in hepatocarcinoma tissues (r=0.683, p<0.05). Survivin expression was positively correlated with VEGF protein expression (r=0.717, p<0.05). There was no significant correlation between HIF-1α expression and survivin expression (p>0.05). The relative quantitative value of HIF-1α, surviving, and VEGF in hepatocarcinoma tissues of hepatocarcinoma group was respectively 3.04±0.23, 2.26±0.31, and 2.57±0.36, significantly higher than that in cancer adjacent liver tissues of control group which was 1.07±0.17, 1.31±0.27, and 1.42±0.43, and the differences were statistically significant (p<0.05). From Western blot electrophoresis scanning, it could be seen that the expressions of HIF-1α, surviving, and VEGF in hepatocarcinoma tissues were higher than those in cancer adjacent normal liver tissues.
CONCLUSIONS
The expressions of HIF-1α, surviving, and VEGF played important roles in the occurrence, invasion, and metastasis of hepatocarcinoma. In hepatocarcinoma tissues, HIF-1α, and survivin protein expression was positively correlated with VEGF expression, but survivin protein was not related to HIF-1α expression, which indicated that HIF-1α and survivin may inhibit the apoptosis of hepatocarcinoma cells and promote tumor angiogenesis by up-regulating the expression of VEGF protein, thus accelerating the occurrence and development of hepatocarcinoma.
Topics: Adult; Aged; Carcinoma, Hepatocellular; Case-Control Studies; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Liver Neoplasms; Male; Middle Aged; Neovascularization, Pathologic; Survivin; Up-Regulation; Vascular Endothelial Growth Factor A
PubMed: 29917189
DOI: 10.26355/eurrev_201806_15159 -
Asian Pacific Journal of Cancer... Sep 2023This study aimed to evaluate the expression of class III β-tubulin (TUBB3), ribonucleoside-diphosphate reductase 1 (RRM1), apurinic/apyrimidinic endonuclease 1 (APE1),...
BACKGROUND
This study aimed to evaluate the expression of class III β-tubulin (TUBB3), ribonucleoside-diphosphate reductase 1 (RRM1), apurinic/apyrimidinic endonuclease 1 (APE1), and survivin in patients with advanced non-small cell lung cancer (NSCLC) to predict response to chemotherapy.
METHODS
TUBB3, RRM1, APE1, and survivin expression levels were determined using immunohistochemistry. Protein expression was validated in Car/Pac-resistant human H1792 and A549 cells. This study included 86 patients, among whom 34 received cisplatin (Cis)/gemcitabine (Gem) and 52 received carboplatin (Car)/paclitaxel (Pac).
RESULTS
Patients with low TUBB3 expression and high RRM1 and survivin expression had higher response rates than those with low RRM1 and survivin expression and high TUBB3 expression in the Car/Pac regimen. The multivariate analysis indicated that TUBB3 and RRM1 were significant independent predictive biomarkers for the Car/Pac regimen; however, there was no association between any protein and overall response in patients treated with this regimen. In the Cis/Gem regimen, only high TUBB3 expression was associated with poor overall survival; however, it did not exhibit a prognostic ability.
CONCLUSION
The expression levels of TUBB3 and RRM1 in NSCLC cells are potential predictive biomarkers, but not prognostic factors, of response to chemotherapy in patients with NSCLC receiving the Car/Pac regimen.
Topics: Humans; Biomarkers, Tumor; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cisplatin; Deoxycytidine; DNA-Binding Proteins; Endonucleases; Lung Neoplasms; Paclitaxel; Prognosis; Ribonucleoside Diphosphate Reductase; Survivin; Tubulin; Tumor Suppressor Proteins
PubMed: 37774051
DOI: 10.31557/APJCP.2023.24.9.3003 -
Seminars in Cell & Developmental Biology Mar 2015Although technically a member of the Inhibitor of Apoptosis (IAP) gene family, survivin has consistently defied assumptions, refuted predictions and challenged... (Review)
Review
Although technically a member of the Inhibitor of Apoptosis (IAP) gene family, survivin has consistently defied assumptions, refuted predictions and challenged paradigms. Despite its more than 5500 citations currently in Medline, the biology of survivin has remained fascinatingly complex, its exploitation in human disease, most notably cancer, tantalizing, and its regulation of cellular homeostasis unexpectedly far-reaching. An inconvenient outsider that resists schemes and dogmas, survivin continues to hold great promise to unlock fundamental circuitries of cellular functions in health and disease.
Topics: Animals; Cell Division; Cell Survival; Humans; Inhibitor of Apoptosis Proteins; Neoplasms; Protein Processing, Post-Translational; Signal Transduction; Survivin
PubMed: 25591986
DOI: 10.1016/j.semcdb.2014.12.007 -
Molecular Cancer Research : MCR Nov 2023In this study, we identify USP1 as a transcriptional target of EWS::FLI1 and demonstrate the requisite function of USP1 in Ewing sarcoma (EWS) cell survival in response...
UNLABELLED
In this study, we identify USP1 as a transcriptional target of EWS::FLI1 and demonstrate the requisite function of USP1 in Ewing sarcoma (EWS) cell survival in response to endogenous replication stress. EWS::FLI1 oncogenic transcription factor drives most EWS, a pediatric bone cancer. EWS cells display elevated levels of R-loops and replication stress. The mechanism by which EWS cells override activation of apoptosis or cellular senescence in response to increased replication stress is not known. We show that USP1 is overexpressed in EWS and EWS::FLI1 regulates USP1 transcript levels. USP1 knockdown or inhibition arrests EWS cell growth and induces cell death by apoptosis. Mechanistically, USP1 regulates Survivin (BIRC5/API4) protein stability and the activation of caspase-9 and caspase-3/7 in response to endogenous replication stress. Notably, USP1 inhibition sensitizes cells to doxorubicin and etoposide treatment. Together, our study demonstrates that USP1 is regulated by EWS::FLI1, the USP1-Survivin axis promotes EWS cell survival, and USP1 inhibition sensitizes cells to standard of care chemotherapy.
IMPLICATIONS
High USP1 and replication stress levels driven by EWS::FLI1 transcription factor in EWS are vulnerabilities that can be exploited to improve existing treatment avenues and overcome drug resistance.
Topics: Humans; Child; Sarcoma, Ewing; Proto-Oncogene Protein c-fli-1; Survivin; RNA-Binding Protein EWS; Cell Line, Tumor; Oncogene Proteins, Fusion; Gene Expression Regulation, Neoplastic; Ubiquitin-Specific Proteases
PubMed: 37478161
DOI: 10.1158/1541-7786.MCR-23-0323 -
Cellular & Molecular Biology Letters 2017Squamous cell carcinoma (SCC) is the most common cancer worldwide. The treatment of locally advanced disease generally requires various combinations of radiotherapy,... (Review)
Review
Squamous cell carcinoma (SCC) is the most common cancer worldwide. The treatment of locally advanced disease generally requires various combinations of radiotherapy, surgery, and systemic therapy. Despite aggressive multimodal treatment, most of the patients relapse. Identification of molecules that sustain cancer cell growth and survival has made molecular targeting a feasible therapeutic strategy. Survivin is a member of the Inhibitor of Apoptosis Protein (IAP) family, which is overexpressed in most of the malignancies including SCC and totally absent in most of the normal tissues. This feature makes survivin an ideal target for cancer therapy. It orchestrates several important mechanisms to support cancer cell survival including inhibition of apoptosis and regulation of cell division. Overexpression of survivin in tumors is also associated with poor prognosis, aggressive tumor behavior, resistance to therapy, and high tumor recurrence. Various strategies have been developed to target survivin expression in cancer cells, and their effects on apoptosis induction and tumor growth attenuation have been demonstrated. In this review, we discuss recent advances in therapeutic potential of survivin in cancer treatment.
Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Cell Proliferation; Humans; Inhibitor of Apoptosis Proteins; Survivin
PubMed: 28536639
DOI: 10.1186/s11658-017-0038-0 -
Veterinary Pathology Mar 2019Canine prostatic carcinoma is a relevant model for human prostatic carcinoma. Survivin is proposed as a biomarker of malignancy in human prostatic cancer. Sox9 is a stem...
Canine prostatic carcinoma is a relevant model for human prostatic carcinoma. Survivin is proposed as a biomarker of malignancy in human prostatic cancer. Sox9 is a stem cell marker required for prostate development and expressed in several adult tissues. The aims of the present study were to evaluate the patterns and expression levels of 2 putative stem cell markers, survivin and Sox9, in canine benign prostatic hyperplasia (BPH) and prostatic carcinoma to investigate their potential as stem cell markers. Immunohistochemistry with specific antibodies was performed on 3 samples of normal prostate gland, 18 samples of canine BPH, and 16 samples of prostatic carcinoma. The basal cell layer of normal and hyperplastic prostatic lobules had nuclear Sox9 immunolabeling and nuclear and rarely cytoplasmic survivin immunostaining, identifying them as potential stem cell markers. Significantly more frequent survivin and Sox9 expression (≥10% of nuclei) was observed in prostatic carcinoma as compared with BPH. The potential coexpression of survivin with Sox9, androgen receptor, and p63 was also investigated in selected BPH and prostatic carcinoma cases with immunofluorescence, and a partial colocalization was observed. Results indicate that Sox9 and survivin could be considered markers of stemness in canine prostate cells. Given its role in proliferation, cells in the basal cell layer with nuclear survivin expression are likely to be transit-amplifying cells that maintain some stem cell proprieties.
Topics: Animals; Biomarkers, Tumor; Dog Diseases; Dogs; Fluorescent Antibody Technique; Male; Prostate; Prostatic Neoplasms; SOX9 Transcription Factor; Stem Cells; Survivin
PubMed: 30131013
DOI: 10.1177/0300985818794161 -
European Journal of Pharmacology Dec 2020Melanoma is a type of skin cancer with an elevated incidence of metastasis and chemoresistance. Such features hamper treatment success of these neoplasms, demanding the...
Melanoma is a type of skin cancer with an elevated incidence of metastasis and chemoresistance. Such features hamper treatment success of these neoplasms, demanding the search for new therapeutic options. Using a two-step resin-based approach, we recently demonstrated that cytotoxic prodiginines bind to the inhibitor of apoptosis protein, survivin. Herein, we explore the role of survivin in melanoma and whether its modulation is related to the antimelanoma properties of three cytotoxic prodiginines (prodigiosin, cyclononylprodigiosin, and nonylprodigiosin) isolated from marine bacteria. In melanoma patients and cell lines, survivin is overexpressed, and higher levels negatively impact survival. All three prodiginines caused a decrease in cell growth with reduced cytotoxicity after 24 h compared to 72 h treatment, suggesting that low concentrations promote cytostatic effects in SK-Mel-19 (BRAF mutant) and SK-Mel-28 (BRAF mutant), but not in SK-Mel-147 (NRAS mutant). An increase in G1 population was observed after 24 h treatment with prodigiosin and cyclononylprodigiosin in SK-Mel-19. Further studies indicate that prodigiosin induced apoptosis and DNA damage, as detected by increased caspase-3 cleavage and histone H2AX phosphorylation, further arguing for the downregulation of survivin. Computer simulations suggest that prodigiosin and cyclononylprodigiosin bind to the BIR domain of survivin. Moreover, knockdown of survivin increased long-term toxicity of prodigiosin, as observed by reduced clonogenic capacity, but did not alter short-term cytotoxicity. In summary, prodiginine treatment provoked cytostatic rather than cytotoxic effects, cell cycle arrest at G0/G1 phase, induction of apoptosis and DNA damage, downregulation of survivin, and decreased clonogenic capacity in survivin knockdown cells.
Topics: Cell Line, Tumor; Cell Survival; DNA Damage; Dose-Response Relationship, Drug; Down-Regulation; Humans; Melanoma; Prodigiosin; Survivin
PubMed: 32814079
DOI: 10.1016/j.ejphar.2020.173465