Smoking and tetramer tryptase accelerate intervertebral disc degeneration by inducing METTL14-mediated DIXDC1 m6 modification.

Although cigarette smoking (CS) and low back pain (LBP) are common worldwide, their correlations and the mechanisms of action remain unclear. We have shown that excessive activation of mast cells (MCs) and their proteases play key roles in CS-associated diseases, like asthma, chronic obstructive pulmonary disease (COPD), blood coagulation, and lung cancer. Previous studies have also shown that MCs and their proteases induce degenerative musculoskeletal disease. By using a custom-designed smoke-exposure mouse system, we demonstrated that CS results in intervertebral disc (IVD) degeneration and release of MC-restricted tetramer tryptases (TTs) in the IVDs. TTs were found to regulate the expression of methyltransferase 14 (METTL14) at the epigenetic level by inducing N6-methyladenosine (m6A) deposition in the 3' untranslated region (UTR) of the transcript that encodes dishevelled-axin (DIX) domain-containing 1 (DIXDC1). That reaction increases the mRNA stability and expression of Dixdc1. DIXDC1 functionally interacts with disrupted in schizophrenia 1 (DISC1) to accelerate the degeneration and senescence of nucleus pulposus (NP) cells by activating a canonical Wnt pathway. Our study demonstrates the association between CS, MC-derived TTs, and LBP. These findings raise the possibility that METTL14-medicated DIXDC1 m6A modification could serve as a potential therapeutic target to block the development of degeneration of the NP in LBP patients.

Inhibition of PI3K/Akt/mTOR signaling pathway alleviates ovarian cancer chemoresistance through reversing epithelial-mesenchymal transition and decreasing cancer stem cell marker expression.

BACKGROUND: Ovarian cancer is the most common malignant tumor of the female reproductive tract. Chemoresistance is a major challenge for current ovarian cancer therapy. However, the mechanism underlying epithelial ovarian cancer (EOC) chemoresistance is not completely uncovered. The phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling is an important intracellular pathway in regulating cell cycle, quiescence, and proliferation. The aim of this study is to investigate the role of PI3K/Akt/mTOR signaling pathway and its association with epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) marker expression in EOC chemoresistance. METHODS: The expressions of EMT and CSC markers were detected by immunofluorescence, western blot, and quantitative real-time PCR. BEZ235, a dual PI3K/mTOR inhibitor, was employed to investigate the role of PI3K/Akt/ mTOR signaling in regulating EMT and CSC marker expression. Students' t test and one-way ANOVA with Tukey's post-hoc test were used to compare the data from different groups. RESULTS: We found that EMT and CSC marker expression were significantly enhanced in chemoresistant EOC cells, which was accompanied by the activation of PI3K/Akt/mTOR signaling. Compared with single cisplatin treatment, combined treatment with BEZ235 and cisplatin significantly disrupted the colony formation ability, induced higher ROS level and more apoptosis in chemoresistant EOC cells. Furthermore, the combination approach effectively inhibited PI3K/Akt/mTOR signaling pathway, reversed EMT, and decreased CSC marker expression in chemoresistant EOC cells compared with cisplatin mono-treatment. CONCLUSIONS: Our results first demonstrate that EMT and enhanced CSC marker expression triggered by activated PI3K/Akt/mTOR signaling are involved in the chemoresistance of EOC, and BEZ235 in combination with cisplatin might be a promising treatment option to reverse EOC chemoresistance.

Valproate induced hepatic steatosis by enhanced fatty acid uptake and triglyceride synthesis.

Steatosis is the characteristic type of VPA-induced hepatotoxicity and may result in life-threatening hepatic lesion. Approximately 61% of patients treated with VPA have been diagnosed with hepatic steatosis through ultrasound examination. However, the mechanisms underlying VPA-induced intracellular fat accumulation are not yet fully understood. Here we demonstrated the involvement of fatty acid uptake and lipogenesis in VPA-induced hepatic steatosis in vitro and in vivo by using quantitative real-time PCR (qRT-PCR) analysis, western blotting analysis, fatty acid uptake assays, Nile Red staining assays, and Oil Red O staining assays. Specifically, we found that the expression of cluster of differentiation 36 (CD36), an important fatty acid transport, and diacylglycerol acyltransferase 2 (DGAT2) were significantly up-regulated in HepG2 cells and livers of C57B/6J mice after treatment with VPA. Furthermore, VPA treatment remarkably enhanced the efficiency of fatty acid uptake mediated by CD36, while this effect was abolished by the interference with CD36-specific siRNA. Also, VPA treatment significantly increased DGAT2 expression as a result of the inhibition of mitogen-activated protein kinase kinase (MEK) - extracellular regulated kinase (ERK) pathway; however, DGAT2 knockdown significantly alleviated VPA-induced intracellular lipid accumulation. Additionally, we also found that sterol regulatory element binding protein-1c (SREBP-1c)-mediated fatty acid synthesis may be not involved in VPA-induced hepatic steatosis. Overall, VPA-triggered over-regulation of CD36 and DGAT2 could be helpful for a better understanding of the mechanisms underlying VPA-induced hepatic steatosis and may offer novel therapeutic strategies to combat VPA-induced hepatotoxicity.

Emerging role of NRF2 in chemoresistance by regulating drug-metabolizing enzymes and efflux transporters.

Chemoresistance is a disturbing barrier in cancer therapy, which always results in limited therapeutic options and unfavorable prognosis. Nuclear factor E2-related factor 2 (NRF2) controls the expression of genes encoding cytoprotective enzymes and transporters that protect against oxidative stress and electrophilic injury to maintain intrinsic redox homeostasis. However, recent studies have demonstrated that aberrant activation of NRF2 due to genetic and/or epigenetic mutations in tumor contributes to the high expression of phase I and phase II drug-metabolizing enzymes, phase III transporters, and other cytoprotective proteins, which leads to the decreased therapeutic efficacy of anticancer drugs through biotransformation or extrusion during chemotherapy. Therefore, a better understanding of the role of NRF2 in regulation of these enzymes and transporters in tumors is necessary to find new strategies that improve chemotherapeutic efficacy. In this review, we summarized the recent findings about the chemoresistance-promoting role of NRF2, NRF2-regulated phase I and phase II drug-metabolizing enzymes, phase III drug efflux transporters, and other cytoprotective genes. Most importantly, the potential of NRF2 was proposed to counteract drug resistance in cancer treatment.

Cryptotanshinone Reverses Cisplatin Resistance of Human Lung Carcinoma A549 Cells through Down-Regulating Nrf2 Pathway.

BACKGROUND/AIMS: To explore whether Nrf2 was associated with drug-resistance in cisplatin resistant A549 (A549/DDP) cells, and if cryptotanshinone (CTS), one of the bioactive compounds isolated from the roots of Salvia miltiorrhiza Bunge (Danshen), could enhance the sensitivity in A549/DDP cells towards cisplatin. METHODS: A549 and A549/DDP cells were subjected to various treatments, and then Sulforhodamine B (SRB) assay, flow cytometry analysis and western immunoblotting analysis were applied to determine IC50, apoptotic status and expressions of Nrf2 and its downstream genes. RESULTS: The endogenous expression levels of Nrf2 as well as its target genes including GCLC, GCLM, HO-1, NQO1 and MRP1 were much higher in A549/DDP cells than those of A549 cells and the susceptibility of A549/DDP cells to cisplatin was partially restored by silencing Nrf2. The combination of CTS and cisplatin led to cell death and apoptosis through sensitizing A549/DDP cells towards cisplatin compared with cisplatin mono-treatment, however, this reversal role could be abolished by Nrf2 knockdown. Specifically, CTS obviously diminished Nrf2 expression, thus contributing to the decrease of Nrf2-target genes expression levels. Meanwhile, we also discovered that CTS triggered several other signals involving in chemoresistance such as MAPKs, Akt and STAT3 pathway. CONCLUSION: Our data indicated CTS may be developed as a potential sensitizer cooperating with anticancer drugs to combat chemoresistant carcinoma through the inhibition of the Nrf2 pathway.

Tanshinone IIA acts as a regulator of lipogenesis to overcome osimertinib acquired resistance in lung cancer.

Osimertinib is a novel epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), acting as the first-line medicine for advanced EGFR-mutated NSCLC. Recently, the acquired resistance to osimertinib brings great challenges to the advanced treatment. Therefore, it is in urgent need to find effective strategy to overcome osimertinib acquired resistance. Here, we demonstrated that SREBP pathway-driven lipogenesis was a key mediator to promote osimertinib acquired resistance, and firstly found Tanshinone IIA (Tan IIA), a natural pharmacologically active constituent isolated from Salvia miltiorrhiza, could overcome osimertinib-acquired resistance in vitro and in vivo via inhibiting SREBP pathway-mediated lipid lipogenesis by using LC-MS based cellular lipidomics analysis, quantitative real-time PCR (qRT-PCR) analysis, western blotting analysis, flow cytometry, small interfering RNAs transfection, and membrane fluidity assay et al. The results showed that SREBP1/2-driven lipogenesis was highly activated in osimertinib acquired resistant NSCLC cells, while knockdown or inhibition of SREBP1/2 could restore the sensitivity of NSCLC to osimertinib via altered the proportion of saturated phospholipids and unsaturated phospholipids in osimertinib acquired-resistant cells. Furthermore, Tanshinone IIA (Tan IIA) could reverse the acquired resistance to osimertinib in lung cancer. Mechanically, Tan IIA inhibited SREBP signaling mediated lipogenesis, changed the profiles of saturated phospholipids and unsaturated phospholipids, and thus promoted osimertinib acquired resistant cancer cells to be attacked by oxidative stress-induced damage and reduce the cell membrane fluidity. The reversal effect of Tan IIA on osimertinib acquired resistant NSCLC cells was also confirmed in vivo, which is helpful for the development of strategies to reverse osimertinib acquired resistance.

Single-Cell Transcriptome Profiling Reveals Multicellular Ecosystem of Nucleus Pulposus during Degeneration Progression.

Although degeneration of the nucleus pulposus (NP) is a major contributor to intervertebral disc degeneration (IVDD) and low back pain, the underlying molecular complexity and cellular heterogeneity remain poorly understood. Here, a comprehensive single-cell resolution transcript landscape of human NP is reported. Six novel human NP cells (NPCs) populations are identified by their distinct molecular signatures. The potential functional differences among NPC subpopulations are analyzed. Predictive transcripts, transcriptional factors, and signal pathways with respect to degeneration grades are explored. It is reported that fibroNPCs is the subpopulation for end-stage degeneration. CD90+NPCs are observed to be progenitor cells in degenerative NP tissues. NP-infiltrating immune cells comprise a previously unrecognized diversity of cell types, including granulocytic myeloid-derived suppressor cells (G-MDSCs). Integrin αM (CD11b) and oxidized low density lipoprotein receptor 1 (OLR1) as surface markers of NP-derived G-MDSCs are uncovered. The G-MDSCs are found to be enriched in mildly degenerated (grade II and III) NP tissues compared to severely degenerated (grade IV and V) NP tissues. Their immunosuppressive function and alleviation effects on NPCs' matrix degradation are revealed in vitro. Collectively, this study reveals the NPC-type complexity and phenotypic characteristics in NP, thereby providing new insights and clues for IVDD treatment.

Triple-negative breast cancer therapeutic resistance: Where is the Achilles' heel?

Triple-negative breast cancer (TNBC) shows a higher response rate to systemic therapy compared with other breast cancer subtypes. However, the tumor differentiation of TNBC is poorer, with an early tendency to metastasis and a higher recurrence rate. Relapsed and metastatic TNBCs usually progress more rapidly, showing strong resistance to chemotherapy and radiotherapy. Due to the lack of combinatorial targeted drugs, alternative treatments fail to improve these patient's prognosis and the quality of life. Finding the Achilles' heel of TNBC is critical for patients with advanced TNBC. Here, we summarize the latest advances in the mechanisms underlying TNBC therapeutic resistance, consider how these mechanisms may affect the development and utilization of TNBC targeted drugs, and discuss the rationale of relevant signals as therapeutic targets. Also, we review the clinical trials registered in ClinicalTrial.gov for TNBC patients, which comprehensively reveals current research and development of novel TNBC targeted drugs and future trends.

Immunotherapy for triple-negative breast cancer: A molecular insight into the microenvironment, treatment, and resistance.

Clinicians have very limited options to treat triple-negative breast cancer (TNBC) due to the lack of effective targeted drugs. Recently, the findings of the mechanism underlying tumor-intrinsic immune escape have fueled a wave of studies into immunotherapy in breast cancer (BC). Compared with other BC subtypes, TNBC shows a better response to immunotherapy due to the higher level of tumor mutation burden and lymphocyte infiltration. Thereinto, immune checkpoint inhibitors (ICIs) achieved the first success of immunotherapy for TNBC and are widely utilized with conventional treatments in the neoadjuvant/adjuvant and advanced stages. However, a large number of TNBC patients fail to demonstrate a good response to ICIs, and the acquired resistance to ICI-based therapies is clinically emerging, which is a major challenge for immunotherapy in TNBC. Here we review the latest advances in TNBC immune microenvironment, immunotherapy, and immunotherapeutic resistance and discuss the challenges and potential approaches to improve the clinical benefit of immunotherapy against TNBC.

THOC2 and THOC5 Regulate Stemness and Radioresistance in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Radioresistance and stemness are substantial obstacles to TNBC treatment. The THO complex (THOC) is a subunit of the TRanscription-EXport complex that functions in the coupling of transcription to nascent RNA splicing, elongation, and export. However, its role in regulating TNBC therapeutic resistance is not reported yet. In this study, the authors demonstrate that cancer stem cells are enriched in radioresistant TNBC cells and describe the role of the THOC in regulating TNBC radioresistance and stemness. The authors find that THOC2 and THOC5 are upregulated in radioresistant TNBC cells and associated with a poor prognosis in TNBC patients. Further investigation reveals that THOC2 promotes the stem-like properties and radioresistance of TNBC cells in a THOC5-dependent manner by facilitating the release of sex-determining region Y (SRY)-box transcription factor 2 (SOX2) and homeobox transcription factor (NANOG) transcripts from the nucleus. Silencing THOC2 or THOC5 expression decreases the protein expression of SOX2 and NANOG, depletes the stem-like properties, and causes radiosensitization in these TNBC cells. Moreover, THOC2 or THOC5 depletion blocks the xenograft tumorigenesis and growth of radioresistant TNBC in vivo. These findings uncover the novel correlations of THOC with TNBC stemness and therapeutic resistance, proposing alternative therapeutic strategies against relapsed TNBC.

Activation of the eIF2α/ATF4 axis drives triple-negative breast cancer radioresistance by promoting glutathione biosynthesis.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Radiotherapy is an effective option for the treatment of TNBC; however, acquired radioresistance is a major challenge to the modality. In this study, we show that the integrated stress response (ISR) is the most activated signaling pathway in radioresistant TNBC cells. The constitutive phosphorylation of eIF2α in radioresistant TNBC cells promotes the activation of ATF4 and elicits the transcription of genes implicated in glutathione biosynthesis, including GCLC, SLC7A11, and CTH, which increases the intracellular level of reduced glutathione (GSH) and the scavenging of reactive oxygen species (ROS) after irradiation (IR), leading to a radioresistant phenotype. The cascade is significantly up-regulated in human TNBC tissues and is associated with unfavorable survival in patients. Dephosphorylation of eIF2α increases IR-induced ROS accumulation in radioresistant TNBC cells by disrupting ATF4-mediated GSH biosynthesis and sensitizes them to IR in vitro and in vivo. These findings reveal ISR as a vital mechanism underlying TNBC radioresistance and propose the eIF2α/ATF4 axis as a novel therapeutic target for TNBC treatment.

Cryptotanshinone strengthens the effect of gefitinib against non-small cell lung cancer through inhibiting transketolase.

Lung cancer is the leading cause of cancer-related mortality and causes more than a million deaths per year. Gefitinib is the first-line agent of advanced lung cancer, however, resistance to gefitinib becomes a major problem in clinical application. Transketolase (TKT) is a key enzyme functioning between the oxidative arm and the non-oxidative arm of the pentose phosphate pathway. In this study, we firstly found that the expression of TKT was remarkably up-regulated in NSCLC cells, while the knockdown of TKT could inhibit cell proliferation and enhance the effect of gefitinib on NSCLC cells, which indicated the role of TKT in treating advanced lung cancer. Cryptotanshinone (CTS) is a natural active compound possessing anti-cancer effect. Here we demonstrated that CTS could strengthen the effect of gefitinib on NSCLC cells via inhibition of TKT in vitro and in vivo. Moreover, Nrf2 was involved in the repression of CTS on TKT expression. Collectively, these findings indicated the role of TKT in lung cancer progression and may provide novel therapeutic strategies to overcome resistance to gefitinib. Furthermore, CTS may serve as a new candidate in adjuvant treatment of advanced lung cancer.

Postoperative Adjuvant Chemotherapy Improved the Prognosis in Locally Advanced Cervical Cancer Patients With Optimal Response to Neoadjuvant Chemotherapy.

BACKGROUND: Few studies investigated the effectiveness of adjuvant chemotherapy (ACT) in patients with optimal response to neoadjuvant chemotherapy (NACT), and an optimal number of treatment cycles for these patients remains unknown. METHODS: A total of 261 Chinese patients with FIGO stage IB2-IIB cervical cancer who obtained an optimal response to NACT were included after radical surgery, and the disease-free survival (DFS) and overall survival (OS) of these patients treated with different cycles of postoperative ACT were compared using the Log-rank test and multivariate analysis. RESULTS: We found that the prognosis of optimal responders treated with postoperative ACT was significantly better than those without further adjuvant therapy. The multivariate analysis showed that postoperative ACT was an independent prognostic factor for DFS. However, there was no significant difference in the DFS and OS between patients who had three cycles of ACT and those with six cycles. Further analysis revealed a significant association of six cycles of ACT with the risk of leukopenia, nausea/vomiting, and rash. CONCLUSION: Our data suggest that additional three cycles of ACT after surgery may improve the clinical outcome of optimal responders in terms of DFS, OS, and drug toxicity.

Exosomes and breast cancer drug resistance.

Drug resistance is a daunting challenge in the treatment of breast cancer (BC). Exosomes, as intercellular communicative vectors in the tumor microenvironment, play an important role in BC progression. With the in-depth understanding of tumor heterogeneity, an emerging role of exosomes in drug resistance has attracted extensive attention. The functional proteins or non-coding RNAs contained in exosomes secreted from tumor and stromal cells mediate drug resistance by regulating drug efflux and metabolism, pro-survival signaling, epithelial-mesenchymal transition, stem-like property, and tumor microenvironmental remodeling. In this review, we summarize the underlying associations between exosomes and drug resistance of BC and discuss the unique biogenesis of exosomes, the change of exosome cargo, and the pattern of release by BC cells in response to drug treatment. Moreover, we propose exosome as a candidate biomarker in predicting and monitoring the therapeutic drug response of BC and as a potential target or carrier to reverse the drug resistance of BC.

Chromatin target of protein arginine methyltransferase regulates invasion, chemoresistance, and stemness in epithelial ovarian cancer.

Ovarian cancer is one of the most common gynecological cancers with a high mortality rate in females. Chromatin target of protein arginine methyltransferase (CHTOP) is an important intracellular protein that regulates the transcriptional activation of several oncogenic genes in glioblastomagenesis and controls mature mRNA export as a component of TRanscription-Export complex. However, the role of CHTOP in ovarian cancer is unclear. In the present study, we investigated the correlation between tumor-derived CHTOP expression and prognosis and explored its role in the malignant behaviors of epithelial ovarian cancer cells. We found that higher expression of CHTOP was associated with a lower disease-free survival (DFS) rate in ovarian cancer patients. Also, CHTOP was highly expressed in human ovarian cancer tissues compared with normal and adjacent tissues. Moreover, compared with IGROV-1 cell line, higher expression of CHTOP was also confirmed in the malignant ovarian cancer cell lines (OV-90 and SK-OV-3). Further results from wound-healing and Matrigel assay showed that CHTOP knockdown significantly reduced the migration and invasion ability of OV-90 and SK-OV-3 cells, while colony formation assay and apoptosis detection showed that CHTOP knockdown markedly sensitized OV-90 and SK-OV-3 cells to cisplatin treatment by inducing apoptosis. Additionally, CHTOP silence also remarkably weakened the stemness of OV-90 and SK-OV-3 through inhibiting the protein expressions of several transcriptional or surface markers of cancer stem cells. These findings first suggest that CHTOP, as a highly expressed protein in ovarian cancer, is closely associated with the malignant phenotypes of epithelial ovarian cancer cells, including metastasis, chemoresistance, and stemness, which highlights a promising role of CHTOP in ovarian cancer targeted therapy.

Cancer stem cells in prostate cancer radioresistance.

Cancer stem cells (CSCs) in prostate cancer (CaP) are regarded as major contributors to radioresistance due to complex mechanisms including enhanced DNA repair, increased intracellular reactive oxygen species scavenging, activation of anti-apoptotic pathways, microenvironment hypoxia, epithelial-to-mesenchymal transition (EMT) and autophagy. They are also believed to cause tumour recurrence and metastasis due to their unique capability to survive and replicate the heterogeneity of the original tumour. Finding markers of prostate CSCs (PCSC) for identification, prognostication and targeting is key in enhancing therapeutic and clinical outcomes. Markers such as aldehyde dehydrogenase, CD44, integrins and EMT markers have been proved to show great potential in being sensitive and specific to the presence of PCSCs. Novel therapies such as Hedgehog and Wnt pathway inhibitors, angiogenesis inhibitors and metformin show potential in eliminating PCSCs to improve therapeutic outcomes. Here, we review the current state of the literature regarding mechanisms of PCSC radioresistance, promising PCSC markers and novel PCSC-specific therapeutic approaches and their implications in CaP treatment and prognosis.

Sesamin Enhances Nrf2-Mediated Protective Defense against Oxidative Stress and Inflammation in Colitis via AKT and ERK Activation.

Ulcerative colitis (UC) is a major form of inflammatory bowel disease (IBD) with high incidence and prevalence in many countries. Patients with UC usually suffer from a lifetime of debilitating physical symptoms. Therefore, developing effective therapeutic strategy that can manage this disease better and improve patients' life quality is in urgent need. Sesamin (SSM) is a lignan derived from sesame seeds. In this study, the protective effect of SSM against UC and the underlying mechanism were investigated in vitro and in vivo. Our data showed that SSM protected Caco-2 cells from H2O2-induced oxidative stress injury via GSH-mediated scavenging of reactive oxygen species (ROS). Dual luciferase reporter assay showed that the transcriptional activity of nuclear factor erythroid-related factor 2 (Nrf2) was significantly increased by SSM, and the ability of SSM to activate Nrf2-targeted genes was further confirmed in Caco-2 cells using western blot and quantitative real-time PCR (qRT-PCR). In contrast, Nrf2 knockdown abolished the protective effect of SSM. Additionally, we found that SSM also activated advanced protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) in Caco-2 cells, while either AKT or ERK inhibition can prevent SSM-mediated nuclear translocation of Nrf2. Furthermore, SSM displayed a better protective effect against dextran sulfate sodium- (DSS-) induced UC compared with 5-aminosalicylic acid (5-ASA) in C57BL/6 mice. The enhanced Nrf2 signaling and activated AKT/ERK were also observed in the colon of mice after SSM administration. These results first demonstrate the protective effect of SSM against UC and indicate that the effect is associated with AKT/ERK activation and subsequent Nrf2 signaling enhancement. This study provides a new insight into the medicinal value of SSM and proposes it as a new natural nutrition for better managing the symptoms of UC.

CHTOP in Chemoresistant Epithelial Ovarian Cancer: A Novel and Potential Therapeutic Target.

Objective: Chemoresistance is a major challenge in epithelial ovarian cancer (EOC) treatment. Chromatin target of protein arginine methyltransferase (CHTOP) was identified as a potential biomarker in chemoresistant EOC cell lines using label-free LC-MS/MS quantitative proteomics. Thus, the aim of this study is to investigate the role of CHTOP in chemoresistant EOC and the underlying mechanism. Methods: The expression of CHTOP in human ovarian cancer cells and tissues was detected using immunofluorescence (IF), western blot (WB), and immunohistochemistry (IHC), respectively. Flow cytometry and TUNEL assay were employed to detect the effect of CHTOP knockdown (KD) in chemoresistant EOC cell apoptosis, while colony and sphere formation assays were used to evaluate its effect on cell stemness. The association of CHTOP with cell metastasis was determined using Matrigel invasion and wound-healing assays. Results: The higher level expression of CHTOP protein was found in chemoresistant EOC cells as compared to their sensitive parental cells or normal epithelial ovarian cells. Results from IHC and bioinformatic analysis showed CHTOP was highly expressed in human ovarian cancer tissues and associated with a poor progression-free survival in patients. In addition, CHTOP KD significantly enhanced cisplatin-induced apoptosis, reduced the stemness of chemoresistant EOC cells, and decreased their metastatic potential. Conclusion: Our findings suggest that CHTOP is associated with apoptosis, stemness, and metastasis in chemoresistant EOC cells and might be a promising target to overcome chemoresistance in EOC treatment.

Cancer stem cell in breast cancer therapeutic resistance.

Development of therapeutic resistance and metastasis is a major challenge with current breast cancer (BC) therapy. Mounting evidence suggests that a subpopulation of cancer stem cells (CSCs) contribute to the cancer therapeutic resistance and metastasis, leading to the recurrence and death in patients. Breast cancer stem cells (BCSCs) are not only a consequence of mutations that overactivate the self-renewal ability of normal stem cells or committed progenitors but also a result of the de-differentiation of cancer cells induced by somatic mutations or microenvironmental components under treatment. Eradication of BCSCs may bring hope and relief to patients whose lives are threatened by recurrent BCs. Therefore, a better understanding of the generation, regulatory mechanisms, and identification of CSCs in BC therapeutic resistance and metastasis will be imperative for developing BCSC-targeted strategies. Here we summarize the latest studies about cell surface markers and signalling pathways that sustain the stemness of BCSC and discuss the associations of mechanisms behind these traits with phenotype and behavior changes in BCSCs. More importantly, their implications for future study are also evaluated and potential BCSC-targeted strategies are proposed to break through the limitation of current therapies.