ADAR1 promotes cisplatin resistance in intrahepatic cholangiocarcinoma by regulating BRCA2 expression through A-to-I editing manner.

Aberrant A-to-I RNA editing, mediated by ADAR1 has been found to be associated with increased tumourigenesis and the development of chemotherapy resistance in various types of cancer. Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive malignancy with a poor prognosis, and overcoming chemotherapy resistance poses a significant clinical challenge. This study aimed to clarify the roles of ADAR1 in tumour resistance to cisplatin in iCCA. We discovered that ADAR1 expression is elevated in iCCA patients, particularly in those resistant to cisplatin, and associated with poor clinical outcomes. Downregulation of ADAR1 can increase the sensitivity of iCCA cells to cisplatin treatment, whereas its overexpression has the inverse effect. By integrating RNA sequencing and Sanger sequencing, we identified BRCA2, a critical DNA damage repair gene, as a downstream target of ADAR1 in iCCA. ADAR1 mediates the A-to-I editing in BRCA2 3'UTR, inhibiting miR-3157-5p binding, consequently increasing BRCA2 mRNA and protein levels. Furthermore, ADAR1 enhances cellular DNA damage repair ability and facilitates cisplatin resistance in iCCA cells. Combining ADAR1 targeting with cisplatin treatment markedly enhances the anticancer efficacy of cisplatin. In conclusion, ADAR1 promotes tumour progression and cisplatin resistance of iCCA. ADAR1 targeting could inform the development of innovative combination therapies for iCCA.

Neoadjuvant immunochemotherapy for pulmonary large-cell neuroendocrine carcinoma: case report.

BACKGROUND: Pulmonary large-cell neuroendocrine carcinoma (pLCNEC) represents a rare malignancy characterized by its aggressive behavior and a notably high recurrence rate. Remarkably, there is currently no established standard treatment protocol for this condition. CASE DESCRIPTION: In this report, we present an intriguing case of pLCNEC diagnosed at clinical-stage IIB. This case involves a 64-year-old man with a smoking history spanning four decades. In our approach, we initiated a course of neoadjuvant chemotherapy in combination with pembrolizumab, administered for two cycles prior to surgical resection. This innovative treatment strategy resulted in a significant pathological response, culminating in a major pathological remission (MPR). As of the time of composing this report, the patient has been diligently monitored for 39 months post-surgery, exhibiting no indications of recurrence, and has demonstrated exceptional tolerance to the entire treatment regimen. CONCLUSIONS: We have first reported a clinically successful case of neoadjuvant combination chemotherapy with pembrolizumab in the treatment of pLCNEC. This case offers promising clinical insights and suggests that this therapeutic approach could be a viable option for managing pLCNEC.

Transcription factor ZNF263 enhances EGFR-targeted therapeutic response and reduces residual disease in lung adenocarcinoma.

EGF receptor (EGFR) tyrosine kinase inhibitors (TKIs) have achieved clinical success in lung adenocarcinoma (LUAD). However, tumors often show profound but transient initial response and then gain resistance. We identify transcription factor ZNF263 as being significantly decreased in osimertinib-resistant or drug-tolerant persister LUAD cells and clinical residual tumors. ZNF263 overexpression improves the initial response of cells and delays the formation of persister cells with osimertinib treatment. We further show that ZNF263 binds and recruits DNMT1 to the EGFR gene promoter, suppressing EGFR transcription with DNA hypermethylation. ZNF263 interacts with nuclear EGFR, impairing the EGFR-STAT5 interaction to enhance AURKA expression. Overexpressing ZNF263 also makes tumor cells with wild-type EGFR expression or refractory EGFR mutations more susceptible to EGFR inhibition. More importantly, lentivirus or adeno-associated virus (AAV)-mediated ZNF263 overexpression synergistically suppresses tumor growth and regrowth with osimertinib treatment in xenograft animal models. These findings suggest that enhancing ZNF263 may achieve complete response in LUAD with EGFR-targeted therapies.

MAFF confers vulnerability to cisplatin-based and ionizing radiation treatments by modulating ferroptosis and cell cycle progression in lung adenocarcinoma.

AIMS: Lung cancer is the leading cause of cancer mortality and lung adenocarcinoma (LUAD) accounts for more than half of all lung cancer cases. Tumor elimination is mostly hindered by drug resistance and the mechanisms remain to be explored in LUAD. METHODS: CRISPR screens in cell and murine models and single-cell RNA sequencing were conducted, which identified MAF bZIP transcription factor F (MAFF) as a critical factor regulating tumor growth and treatment resistance in LUAD. RNA and ChIP sequencing analyses were performed for transcriptional target expression and specific binding sites of MAFF. Functions of MAFF in inhibiting tumor growth and promoting cisplatin or irradiation efficacy were investigated using cellular and xenograft models. RESULTS: Patients with lung adenocarcinoma and reduced MAFF expression had worse clinical outcomes. MAFF inhibited tumor cell proliferation by regulating the expression of SLC7A11, CDK6, and CDKN2C, promoting ferroptosis and preventing cell cycle progression from G1 to S. MAFF also conferred tumor cells vulnerable to cisplatin-based or ionizing radiation treatments. MAFF reduction was a final event in the acquisition of cisplatin resistance of LUAD cells. The intracellular cAMP/PKA/CREB1 pathway upregulated MAFF in response to cisplatin-based or ionizing radiation treatments. CONCLUSIONS: MAFF suppresses tumor growth, and pharmacological agonists targeting MAFF may improve cisplatin or irradiation therapies for lung adenocarcinoma patients.

CSNK2A1 confers gemcitabine resistance to pancreatic ductal adenocarcinoma via inducing autophagy.

Gemcitabine, a pivotal chemotherapeutic agent for pancreatic ductal adenocarcinoma (PDAC), frequently encounters drug resistance, posing a significant clinical challenge with implications for PDAC patient prognosis. In this study, employing an integrated approach involving bioinformatic analyses from multiple databases, we unveil CSNK2A1 as a key regulatory factor. The patient-derived xenograft (PDX) model further substantiates the critical role of CSNK2A1 in gemcitabine resistance within the context of PDAC. Additionally, targeted silencing of CSNK2A1 expression significantly enhances sensitivity of PDAC cells to gemcitabine treatment. Mechanistically, CSNK2A1's transcriptional regulation is mediated by H3K27 acetylation in PDAC. Moreover, we identify CSNK2A1 as a pivotal activator of autophagy, and enhanced autophagy drives gemcitabine resistance. Silmitasertib, an established CSNK2A1 inhibitor, can effectively inhibit autophagy. Notably, the combinatorial treatment of Silmitasertib with gemcitabine demonstrates remarkable efficacy in treating PDAC. In summary, our study reveals CSNK2A1 as a potent predictive factor for gemcitabine resistance in PDAC. Moreover, targeted CSNK2A1 inhibition by Silmitasertib represents a promising therapeutic strategy to restore gemcitabine sensitivity in PDAC, offering hope for improved clinical outcomes.

Inhibition of PKA/CREB1 pathway confers sensitivity to ferroptosis in non-small cell lung cancer.

Ferroptosis is a type of regulated cell death characterized by iron accumulation and lipid peroxidation. The molecular mechanisms underlying ferroptosis regulation in non-small cell lung cancer (NSCLC) are poorly understood. In this study, we found that protein kinase A (PKA) inhibition enhanced ferroptosis susceptibility in NSCLC cells, as evidenced by reduced cell viability and increased lipid peroxidation. We further identified cAMP-responsive element protein 1 (CREB1), a transcription factor and a substrate of PKA, as a key regulator of ferroptosis. Knockdown of CREB1 sensitized NSCLC cells to ferroptosis inducers (FINs) and abolished the effects of PKA inhibitor and agonist, revealing the pivotal role of CREB1 in ferroptosis regulation. Using a high-throughput screening approach and subsequent validation by chromatin immunoprecipitation (ChIP) and dual-luciferase assays, we discovered that CREB1 transcriptionally activated stearoyl-CoA desaturase (SCD), an enzyme that catalyzes the conversion of saturated fatty acids to monounsaturated fatty acids. SCD conferred ferroptosis resistance by decreasing the availability of polyunsaturated fatty acids for lipid peroxidation, and its overexpression rescued the effect of CREB1 knockdown on ferroptosis in vitro. Besides, CREB1 knockdown suppressed xenograft tumor growth in the presence of Imidazole Ketone Erastin (IKE), a potent FIN, and this effect was reversed by SCD. Finally, we showed that high expression of CREB1 was associated with poor prognosis in NSCLC patients from public datasets and our institution. Collectively, this study illustrates the effect of PKA/CREB1/SCD axis in regulating ferroptosis of NSCLC, targeting this pathway may provide new strategies for treating NSCLC patients.

DAGLß is the principal synthesizing enzyme of 2-AG and promotes aggressive phenotype of intrahepatic cholangiocarcinoma via AP-1/DAGLß/miR4516 feedforward circuitry.

The endocannabinoid system (ECS) is dysregulated in various liver diseases. Previously, we had shown that the major endocannabinoid 2-arachidonoyl glycerol (2-AG) promoted tumorigenesis of intrahepatic cholangiocarcinoma (ICC). However, biosynthesis regulation and clinical significance of 2-AG remain elusive. In the present study, we quantified 2-AG by gas chromatography/mass spectrometry (GC/MS) and showed that 2-AG was enriched in patients with ICC samples as well as in thioacetamide-induced orthotopic rat ICC model. Moreover, we found that diacylglycerol lipase ß (DAGLß) was the principal synthesizing enzyme of 2-AG that significantly upregulated in ICC. DAGLß promoted tumorigenesis and metastasis of ICC in vitro and in vivo and positively correlated with clinical stage and poor survival in patients with ICC. Functional studies showed that activator protein-1 (AP-1; heterodimers of c-Jun and FRA1) directly bound to the promoter and regulated transcription of DAGLß, which can be enhanced by lipopolysaccharide (LPS). miR-4516 was identified as the tumor-suppressing miRNA of ICC that can be significantly suppressed by LPS, 2-AG, or ectopic DAGLß overexpression. FRA1 and STAT3 were targets of miR-4516 and overexpression of miRNA-4516 significantly suppressed expression of FRA1, SATA3, and DAGLß. Expression of miRNA-4516 was negatively correlated with FRA1, SATA3, and DAGLß in patients with ICC samples. Our findings identify DAGLß as the principal synthesizing enzyme of 2-AG in ICC. DAGLß promotes oncogenesis and metastasis of ICC and is transcriptionally regulated by a novel AP-1/DAGLß/miR4516 feedforward circuitry.NEW & NOTEWORTHY Dysregulated endocannabinoid system (ECS) had been confirmed in various liver diseases. However, regulation and function of 2-arachidonoyl glycerol (2-AG) and diacylglycerol lipase ß (DAGLß) in intrahepatic cholangiocarcinoma (ICC) remain to be elucidated. Here, we demonstrated that 2-AG was enriched in ICC, and DAGLß was the principal synthesizing enzyme of 2-AG in ICC. DAGLß promotes tumorigenesis and metastasis in ICC via a novel activator protein-1 (AP-1)/DAGLß/miR4516 feedforward circuitry.

KLF11 regulates lung adenocarcinoma ferroptosis and chemosensitivity by suppressing GPX4.

Ferroptosis, an iron-dependent non-apoptotic cell death, has been shown to play a vital role in tumor proliferation and chemotherapy resistance. Here, we report that KLF11 inhibits lung adenocarcinoma (LUAD) cell proliferation and promotes chemotherapy sensitivity by participating in the GPX4-related ferroptosis pathway. Through an RNA-sequence screen from LUAD cells pretreatment with ferroptosis inducers (FINs), we discovered that KLF11 expression was significantly higher in FINs-treated cells, suggesting that KLF11 may be involved in ferroptosis. Overexpression of KLF11 promoted LUAD cells to undergo ferroptosis alterations. Meanwhile, upregulation of KLF11 expression also inhibited cell proliferation and increased chemosensitivity, whereas knockout of KLF11 did the opposite. With ChIP-Seq and RNA-Seq, we identified GPX4 as a downstream target of KLF11. Through ChIP-qPCR and dual luciferase assay, we clarified that KLF11 binds to the promoter region of GPX4 and represses its transcription. Restored GPX4 expression antagonized the ability of KLF11 to promote ferroptosis, increase chemotherapy sensitivity and inhibit cell proliferation in vitro and in vivo. Clinically, KLF11 declined in LUAD and its low expression was associated with reduced patient survival. Our findings established the function of KLF11 to promote ferroptosis in LUAD, thereby inhibiting cell proliferation and enhancing the efficacy of chemotherapy.

HNF4G increases cisplatin resistance in lung adenocarcinoma via the MAPK6/Akt pathway.

Background: Lung adenocarcinoma is one of the most common tumors, and cisplatin is frequently used in treating lung adenocarcinoma patients. This study aimed to look into the roles and mechanisms of HNF4G in cisplatin resistance of lung adenocarcinoma. Materials & Methods: Cisplatin resistance and gene expression data of 542 cell lines from the CTRP and CCLE databases were analyzed. HNF4G expression was detected in the lung adenocarcinoma cell lines after treatment with various concentrations of cisplatin. Cisplatin sensitivity curves were detected in cells that overexpressed or knocked down HNF4G. The ChIP-Seq data were then analyzed to identify the targets of HNF4G involved in cisplatin resistance. Expression and phosphorylation of the MAPK6/Akt pathway were detected after HNF4G was overexpressed or knocked down. Finally, ChIP-qPCR and dual-luciferase assays were used to investigate the regulation of HNF4G on MAPK6. Results: In cell lines, high expression of HNF4G was significantly positively correlated with cisplatin resistance, and lung adenocarcinoma patients who had high HNF4G expression had a poor prognosis. Cisplatin treatment increased HNF4G expression, and overexpression of HNF4G significantly increased the resistance to cisplatin in A549 and HCC827 cells, whereas knockdown of HNF4G had the opposite effect. HNF4G overexpression increased MAPK6 expression and activated the MAPK6/Akt pathway, while an Akt inhibitor reduced the effects of HNF4G on cisplatin resistance. HNF4G bound to the MAPK6 promoter region, promoting MAPK6 expression, according to ChIP-qPCR and luciferase assays. Conclusion: By binding to the MAPK6 promoter region, HNF4G promotes MAPK6 expression and subsequent Akt phosphorylation, resulting in resistance to cisplatin in lung adenocarcinoma.

Neoadjuvant pembrolizumab and chemotherapy in resectable clinical stage III non-small-cell lung cancer: a retrospective cohort study.

Background: Pembrolizumab has been shown to be effective and safe in improving the survival of patients with advanced non-small-cell lung cancer (NSCLC). However, the effectiveness and safty of pembrolizumab in the induction treatment of patients with potential resectable clinical stage III NSCLC remains undetermined. Methods: A total of 25 patients who received neoadjuvant pembrolizumab plus chemotherapy for preoperative stage III NSCLC between August 2020 and November 2021 in Zhongshan Hospital were retrospectively evaluated, and 21 of them were followed by pulmonary resection. The neoadjuvant treatment was as follows: intravenous pembrolizumab (200 mg) on day 1, carboplatin [target area under the curve (AUC) 5 mg/mL] or cisplatin (75 mg/m2) on day 1, and pemetrexed (500 mg/m2 for adenocarcinoma) or nab-paclitaxel (260 mg/m2 for other subtypes) on day 1 of every 21-day cycle up to two or three cycles. Results: The mean age of all 25 patients was 65 years, of whom 22 were men and 3 were women. Seventeen were diagnosed before treatment as clinical stage IIIA, seven as IIIB, and one as IIB. All received neoadjuvant immunotherapy plus chemotherapy. Following induction therapy, 21 patients with stable disease or partial response (PR) according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) underwent surgical resection without delay. Among the patients who underwent operation, major pathological response (MPR) was achieved in 13 patients, including 6 (28.6%) patients achieved a complete pathological response (CPR). Two patients with partial radiologic remission refused operative treatment, one had progressive disease (PD), and another developed a grade immune pneumonia and could not tolerate surgery. However, none of the adverse events caused surgery delays or deaths. Conclusions: Neoadjuvant pembrolizumab plus chemotherapy could be considered reliable for clinical stage III NSCLC, but needs to be validated with more robust clinical trials.

Imatinib facilitates gemcitabine sensitivity by targeting epigenetically activated PDGFC signaling in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with poor prognosis. Gemcitabine-based chemotherapy has become one of the main modalities of its management. However, gemcitabine resistance frequently occurs, leading to failure of PDAC therapy. Platelet-derived growth factors (PDGFs) and their receptors play important roles in cancer progression and chemoresistance. We aimed to investigate the biological function and therapeutic significance of platelet-derived growth factor C (PDGFC) in drug-resistant PDAC. Our study showed that PDGFC was abnormally highly expressed in gemcitabine-resistant PDAC. Silencing PDGFC expression can enhance the therapeutic effect of gemcitabine on PDAC. Mechanistically, the transcription of PDGFC is mediated by H3K27 acetylation, and PDGFC promotes gemcitabine resistance by activating the PDGFR-PI3K-AKT signaling pathway. The PDGFR inhibitor imatinib inhibits the PDGFR pathway. Imatinib and gemcitabine have a synergistic effect on the treatment of PDAC, and imatinib can significantly enhance the anti-tumor effect of gemcitabine in a drug-resistant PDAC patient-derived xenograft model. In conclusion, PDGFC is a potential predictor of gemcitabine-resistant PDAC. Imatinib inhibits PDGFR activation to promote gemcitabine sensitivity in PDAC. Combined modality regimen of imatinib and gemcitabine is likely to translate into clinical trial for the treatment of PDGFC-associated gemcitabine-resistant patients.

YTHDF2 promotes intrahepatic cholangiocarcinoma progression and desensitises cisplatin treatment by increasing CDKN1B mRNA degradation.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer with exceedingly poor prognosis, and chemoresistance is a huge challenge for treatment. N6-methyladenosine (m6 A) modification plays an important role in the progression and chemoresistance of cancers. We aimed to investigate the oncogenic function and therapeutic significance of the m6 A binding protein, YTH domain family 2 (YTHDF2), in ICC progression and cisplatin-based chemotherapy. METHODS: Several independent data sets were used to assess the expression of YTHDF2 in ICC, particularly in chemoresistant ICC. Knockdown and overexpression were used to evaluate the effects of YTHDF2 on tumourigenesis and cisplatin response in ICC. Multi-omics sequencing was performed to identify target genes. RIP, dual luciferase reporter, RNA stability experiment and loss-of-function assays were conducted to study the mechanisms underlying the oncogenic function of YTHDF2. Furthermore, patient-derived xenograft (PDX) model was established to determine the effect of combination treatment of YTHDF2 siRNA and cisplatin in ICC. RESULTS: Our study showed that YTHDF2 was upregulated in ICC tissues, particularly in chemoresistant ICC tissues, and correlated with poor prognosis. Furthermore, silencing YTHDF2 led to inhibited proliferation, promoted apoptosis and G0/G1 cell cycle arrest. Its downregulation also enhanced DNA damage and sensitised ICC cells to cisplatin. YTHDF2 overexpression exerted the opposite results. Integration analysis using RNA-seq, MeRIP-seq and anti-YTHDF2 RIP-seq elucidated the role of YTHDF2 in tumourigenesis and cisplatin-desensitising function by promoting the degradation of cyclin-dependent kinase inhibitor 1B (CDKN1B) mRNA in an m6 A-dependent manner. Downregulation of CDKN1B increased the YTHDF2 silencing-induced influence on tumourigenesis and cisplatin response to ICC. In addition, the combination treatment of YTHDF2 siRNA and cisplatin significantly enhanced the anti-tumour effect of cisplatin in a chemoresistant ICC PDX model. CONCLUSIONS: YTHDF2 exhibits tumour oncogenic and cisplatin-desensitising properties, which may offer insight into the development of novel combination therapeutic strategies for ICC.

Cardiac ISL1-Interacting Protein, a Cardioprotective Factor, Inhibits the Transition From Cardiac Hypertrophy to Heart Failure.

Heart failure is characterized by the inability of the heart to pump effectively and generate proper blood circulation to meet the body's needs; it is a devastating condition that affects more than 100 million people globally. In spite of this, little is known about the mechanisms regulating the transition from cardiac hypertrophy to heart failure. Previously, we identified a cardiomyocyte-enriched gene, CIP, which regulates cardiac homeostasis under pathological stimulation. Here, we show that the cardiac transcriptional factor GATA4 binds the promotor of CIP gene and regulates its expression. We further determined that both CIP mRNA and protein decrease in diseased human hearts. In a mouse model, induced cardiac-specific overexpression of CIP after the establishment of cardiac hypertrophy protects the heart by inhibiting disease progression toward heart failure. Transcriptome analyses revealed that the IGF, mTORC2 and TGFß signaling pathways mediate the inhibitory function of CIP on pathologic cardiac remodeling. Our study demonstrates GATA4 as an upstream regulator of CIP gene expression in cardiomyocytes, as well as the clinical significance of CIP expression in human heart disease. More importantly, our investigation suggests CIP is a key regulator of the transition from cardiac hypertrophy to heart failure. The ability of CIP to intervene in the onset of heart failure suggests a novel therapeutic avenue of investigation for the prevention of heart disease progression.

A PDX model combined with CD-DST assay to evaluate the antitumor properties of KRpep-2d and oxaliplatin in KRAS (G12D) mutant colorectal cancer.

Patient-derived xenograft (PDX) models are more faithful in maintaining the characteristics of human tumors than cell lines and are widely used in drug development, although they have some disadvantages, including their relative low success rate, long turn-around time, and high costs. The collagen gel droplet embedded culture drug sensitivity test (CD-DST) has been used as an in-vitro drug sensitivity test for patients with cancer because of its high success rate of primary cell culture, high sensitivity, and good clinical relevance, but it is based on an in-vitro cell culture and may not simulate the tumor microenvironment accurately. This study aims to combine a PDX model with CD-DST to evaluate the efficiency of antitumor agents. KRpep-2d, a small peptide targeting KRAS (G12D), and oxaliplatin were used to verify the feasibility of this approach. Whole-exome sequencing and Sanger sequencing were first applied to test and validate the KRAS mutation status of a panel of colorectal cancer PDX tissues. One PDX model was verified to carry KRAS (G12D) mutation and was used for in-vivo and the CD-DST drug tests. We then established the PDX mouse model from the patient with the KRAS (G12D) mutation and obtained viable cancer cells derived from the same PDX model. Next, the antitumor abilities of KRpep-2d and oxaliplatin were estimated in the PDX model and the CD-DST. We found that KRpep-2d showed no significant antitumor effect on the xenograft model or on cancer cells derived from the same PDX model. In contrast, oxaliplatin showed significant inhibitory effects in both tests. In conclusion, the PDX model in combination with the CD-DST assay is a comprehensive and feasible method of evaluating the antitumor properties of compounds and could be applied for new drug discovery.

Ailanthus Altissima-derived Ailanthone enhances Gastric Cancer Cell Apoptosis by Inducing the Repression of Base Excision Repair by Downregulating p23 Expression.

Chemotherapy plays an irreplaceable role in the treatment of GC, but currently available chemotherapeutic drugs are not ideal. The application of medicinal plants is an important direction for new drug discovery. Through drug screening of GC organoids, we determined that ailanthone has an anticancer effect on GC cells in vitro and in vivo. We also found that AIL can induce DNA damage and apoptosis in GC cells. Further transcriptome sequencing of PDX tissue indicated that AIL inhibited the expression of XRCC1, which plays an important role in DNA damage repair, and the results were also confirmed by western blotting. In addition, we found that AIL inhibited the expression of P23 and that inhibition of P23 decreased the expression of XRCC1, indicating that AIL can regulate XRCC1 via P23. The results of coimmunoprecipitation showed that AIL can inhibit the binding of P23 and XRCC1 to HSP90. These findings indicate that AIL can induce DNA damage and apoptosis in GC cells. Meanwhile, AIL can decrease XRCC1 activity by downregulating P23 expression to inhibit DNA damage repair. The present study sheds light on the potential application of new drugs isolated from natural medicinal plants for GC therapy.

ATM/NEMO signaling modulates the expression of PD-L1 following docetaxel chemotherapy in prostate cancer.

BACKGROUND: The efficacy of docetaxel-based chemotherapy is limited by the development of drug resistance. Recent studies demonstrated the efficacy of anti-programmed death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) immunotherapies in metastatic prostate cancer. The ataxia telangiectasia mutation (ATM) protein plays a crucial role in maintaining genome stability and function of mitosis. Here, we aimed to determine whether PD-1/PD-L1 signaling contributes to the resistance to DTX and to elucidate the mechanism underlying DTX-induced PD-L1 expression. METHODS: In this retrospective study, PD-L1 expression was analyzed in 33 tumor tissue samples from prostate cancer patients. Prostate cell lines were used to perform functional assays and examine underlying mechanisms in vitro. A fully mouse prostate cancer model and a humanized chimeric mouse bearing human prostate tumors and peripheral blood mononuclear cells were used for in vivo assays. RESULTS: We have shown that DTX, a chemotherapeutic drug which causing microtubule interference, could significantly induce the expression of PD-L1 in prostate cancer cells. This effect is blocked by the inhibition of ATM, suggesting that it plays an essential role in PD-L1 expression upregulated by DTX. Mechanistic studies have shown that ATM activity in cancer cells enhances the stability of the NF-κB essential modulator (NEMO), which leading to an increase in the NF-κB activity and PD-L1 expression. Using the mouse model, it was further demonstrated that a combination of ATM and NEMO inhibitors along with DTX augmented the antitumor efficacy of chemotherapy, which are comparable to that of PD-L1 antibody. CONCLUSIONS: Our findings have revealed that a previously unrecognized ATM-NEMO signaling which induced by DTX is capable of suppressing tumor immunity by activating the expression of PD-L1, suggesting that the ATM-NEMO-NF-κB axis can be exploited to restore the immune balance and overcome cancer resistance triggered by DTX.Graphic Abstract: supplementary file 1.

LncRNA SNHG19 Promotes the Development of Non-Small Cell Lung Cancer via Mediating miR-137/E2F7 Axis.

OBJECTIVE: Non-small cell lung cancer (NSCLC) is a common malignant tumor, which has high incidence and low the 5-year survival rate. Long non-coding RNAs (lncRNAs) play critical roles in carcinoma occurrence and metastasis. Herein, our aim was to investigate the effects of lncRNA SNHG19 in NSCLC progression. MATERIALS AND METHODS: Long non-coding RNA Small Nucleolar RNA Host Gene 19 (lncRNA SNHG19) expression level was measured by bioinformatics and qRT-PCR. Edu, Transwell, and scratch assays were performed to explore the role of si-SNHG19 or SNHG19 on NSCLC progression. Luciferase assay was used to verify the relationship between SNHG19/E2F7 and miR-137. The experiment of Xenograft was used for exploring the function of SNHG19 in vivo. RESULTS: SNHG19 was upregulated in cancer tissues, patients plasma and cell lines of NSCLC. Knockdown of SNHG19 inhibited cell proliferation, migration, and invasion. Luciferase assay confirmed that SNHG19 regulated E2F7 expression via interacting with miR-137. Overexpression of SNHG19 accelerated NSCLC tumor progression via miR-137/E2F7 axis both in vitro and in vivo. CONCLUSIONS: Our results clarified the SNHG19 function for the first time, and SNHG19 promoted the progression of NSCLC, which was mediated by the miR-137/E2F7 axis. This study might provide new understanding and targets for NSCLC diagnosis and treatment.

Home enteral nutrition for postoperative elderly patients with esophageal cancer.

BACKGROUND: The clinical value of enteral nutrition (EN) after radical resection of esophageal cancer (EC) has been well recognized during hospital stay; however, whether using EN agents should be continued at home after the patient is discharged remains unclear, especially for the elderly postoperative patients. Here we investigated the effects of continued EN on nutrition and immune status in elderly patients who had undergone radical EC surgery. METHODS: Sixty eligible elderly patients undergoing surgical treatment for EC in our center during the period from October 2016 to October 2018 were randomly divided into EN group and control groups, with 30 patients in each group. Among them, the EN group continued to take an orally administered EN agent (Ensure®) daily in addition to daily routine diets after discharge; however, patients in the control group only received regular diets after discharge. The nutritional status and immune indicators were evaluated at discharge and 4 and 8 weeks after discharge (weeks 4 and 8) and compared between EN and control groups. RESULTS: Body mass index (BMI), Patient-Generated Subjective Global Assessment (PG-SGA) score, hemoglobin, serum albumin, serum prealbumin, CD4 and CD8 T cell counts, CD4/CD8 ratio, IgA, IgG, and IgM showed no significant difference between EN group and control group at discharge (all P>0.05). In week 4, the serum prealbumin level was significantly higher in the EM group than in the control group (P<0.05). In week eight, the EM group had significantly higher BMI, PG-SGA score, serum albumin, serum prealbumin, CD4 and CD8 T cell counts, CD4/CD8 ratio, IgA, IgG, and IgM than the control group (all P<0.05). CONCLUSIONS: Home EN helps improve immune function in elderly patients who have undergone radical surgery for EC and is worthy of clinical promotion. To optimize its efficacy, a home EN should last no less than eight weeks after discharge.

Eukaryotic translation initiation factor 3B accelerates the progression of esophageal squamous cell carcinoma by activating ß-catenin signaling pathway.

INTRODUCTION: Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignant tumors. Eukaryotic translation initiation factors 3B (EIF3B) is considered to influence tumor proliferation, invasion, apoptosis and cell cycle, which act together to promote the progression of tumors. However, the role of EIF3B in ESCC is unknown. This study aims to explore the clinical and biological role of EIF3B in ESCC. RESULTS: EIF3B expressions were up-regulated in both ESCC tissues and cell lines. Overexpression of EIF3B was associated with tumor depth, lymph node metastasis and advanced TNM stage. Importantly, patients with high EIF3B expression suffered shorter overall and disease-free survival. Knockdown of EIF3B could inhibit cell proliferation and invasion, promote cell apoptosis, and interfere the cell cycle in vitro. EIF3B-knockdown cells could form smaller subcutaneous tumors in vivo. Finally, we demonstrated EIF3B could activate ß-catenin signaling pathway. METHODS: Immunohistochemical staining and Western blot were performed to detect the EIF3B expression in ESCC patient tissues and cell lines. The association between EIF3B expression and patients' prognosis was analyzed by Kaplan-Meier and Cox regression. Then, CCK-8, colony-formation, Transwell and wound-healing assay were performed to compare the bio-functional change after knockdown of EIF3B. Flow cytometry was applied to analyze the change of cell apoptosis and cycle induced by EIF3B knockdown. Tumor xenograft assay was done to verify the in-vitro results. CONCLUSIONS: EIF3B might serve as a novel marker for predicting prognosis of ESCC patients and as a potential therapeutic target, individually or together with other subunits of EIF3 complex.

Regulation of CXCR4/AKT-signaling-induced cell invasion and tumor metastasis by RhoA, Rac-1, and Cdc42 in human esophageal cancer.

CXC chemokines and their cognate receptors have been implicated wildly in cancer pathogenesis. In the present study, we report a critical cause relationship between CXCR4 expression and tumorigenesis in the setting of human esophageal squamous cell carcinoma (ESCC). In ESCC cells, CXCR4 expression was significantly higher than in human esophageal epithelial cells (HEEC). Reduction of CXCR4 in ESCC cells reduced cell proliferation and invasion in vitro and tumor growth in vivo. Among the potential downstream targets of CXCR4-CXCL12 are RhoA, Rac-1, and Cdc42, which are likely to contribute to the invasiveness of ESCC cells. Finally, we found that CXCR4-CXCL12/AKT axis regulates RhoA, Rac-1, and Cdc42 to modulate cell invasion and tumor metastasis. Together, these results demonstrate a role for CXCR4 in ESCC metastasis and progression and suggest potential targets for therapeutic intervention.