HMGA1 sensitizes esophageal squamous cell carcinoma to mTOR inhibitors through the ETS1-FKBP12 axis.

Esophageal carcinoma is amongst the prevalent malignancies worldwide, characterized by unclear molecular classifications and varying clinical outcomes. The PI3K/AKT/mTOR signaling, one of the frequently perturbed dysregulated pathways in human malignancies, has instigated the development of various inhibitory agents targeting this pathway, but many ESCC patients exhibit intrinsic or adaptive resistance to these inhibitors. Here, we aim to explore the reasons for the insensitivity of ESCC patients to mTOR inhibitors. We assessed the sensitivity to rapamycin in various ESCC cell lines by determining their respective IC50 values and found that cells with a low level of HMGA1 were more tolerant to rapamycin. Subsequent experiments have supported this finding. Through a transcriptome sequencing, we identified a crucial downstream effector of HMGA1, FKBP12, and found that FKBP12 was necessary for HMGA1-induced cell sensitivity to rapamycin. HMGA1 interacted with ETS1, and facilitated the transcription of FKBP12. Finally, we validated this regulatory axis in in vivo experiments, where HMGA1 deficiency in transplanted tumors rendered them resistance to rapamycin. Therefore, we speculate that mTOR inhibitor therapy for individuals exhibiting a reduced level of HMGA1 or FKBP12 may not work. Conversely, individuals exhibiting an elevated level of HMGA1 or FKBP12 are more suitable candidates for mTOR inhibitor treatment.

Deprivation of methionine inhibits osteosarcoma growth and metastasis via C1orf112-mediated regulation of mitochondrial functions.

Osteosarcoma is a malignant bone tumor that primarily inflicts the youth. It often metastasizes to the lungs after chemotherapy failure, which eventually shortens patients' lives. Thus, there is a dire clinical need to develop a novel therapy to tackle osteosarcoma metastasis. Methionine dependence is a special metabolic characteristic of most malignant tumor cells that may offer a target pathway for such therapy. Herein, we demonstrated that methionine deficiency restricted the growth and metastasis of cultured human osteosarcoma cells. A genetically engineered Salmonella, SGN1, capable of overexpressing an L-methioninase and hydrolyzing methionine led to significant reduction of methionine and S-adenosyl-methionine (SAM) specifically in tumor tissues, drastically restricted the growth and metastasis in subcutaneous xenograft, orthotopic, and tail vein-injected metastatic models, and prolonged the survival of the model animals. SGN1 also sharply suppressed the growth of patient-derived organoid and xenograft. Methionine restriction in the osteosarcoma cells initiated severe mitochondrial dysfunction, as evident in the dysregulated gene expression of respiratory chains, increased mitochondrial ROS generation, reduced ATP production, decreased basal and maximum respiration, and damaged mitochondrial membrane potential. Transcriptomic and molecular analysis revealed the reduction of C1orf112 expression as a primary mechanism underlies methionine deprivation-initiated suppression on the growth and metastasis as well as mitochondrial functions. Collectively, our findings unraveled a molecular linkage between methionine restriction, mitochondrial function, and osteosarcoma growth and metastasis. A pharmacological agent, such as SGN1, that can achieve tumor specific deprivation of methionine may represent a promising modality against the metastasis of osteosarcoma and potentially other types of sarcomas as well.

Mesothelin CAR-T cells expressing tumor-targeted immunocytokine IL-12 yield durable efficacy and fewer side effects.

Chimeric antigen receptor (CAR)-modified T cell therapy has achieved remarkable efficacy in treating hematological malignancies, but it confronts many challenges in treating solid tumors, such as the immunosuppressive microenvironment of the solid tumors. These factors reduce the antitumor activity of CAR-T cells in clinical trials. Therefore, we used the immunocytokine interleukin-12 (IL-12) to enhance the efficacy of CAR-T cell therapy. In this study, we engineered CAR-IL12R54 T cells that targeted mesothelin (MSLN) and secreted a single-chain IL-12 fused to a scFv fragment R54 that recognized a different epitope on mesothelin. The evaluation of the anti-tumor activity of the CAR-IL12R54 T cells alone or in combination with anti-PD-1 antibody in vitro and in vivo was followed by the exploration of the functional mechanism by which the immunocytokine IL-12 enhanced the antitumor activity. CAR-IL12R54 T cells had potency to lyse mesothelin positive tumor cells in vitro. In vivo studies demonstrated that CAR-IL12R54 T cells were effective in controlling the growth of established tumors in a xenograft mouse model with fewer side effects than CAR-T cells that secreted naked IL-12. Furthermore, combination of PD-1 blockade antibody with CAR-IL12R54 T cells elicited durable anti-tumor responses. Mechanistic studies showed that IL12R54 enhanced Interferon-γ (IFN-γ) production and dampened the activity of regulatory T cells (Tregs). IL12R54 also upregulated CXCR6 expression in the T cells through the NF-κB pathway, which facilitated T cell infiltration and persistence in the tumor tissues. In summary, the studies provide a good therapeutic option for the clinical treatment of solid tumors.

Scoparone attenuates glioma progression and improves the toxicity of temozolomide by suppressing RhoA/ROCK1 signaling.

BACKGROUND: Glioma, a type of malignant brain tumor, has become a challenging health issue globally in recent years. METHODS: In this study, we investigated the potential therapeutic role of scoparone in glioma and the underlying mechanism. Initially, transcriptome sequencing was conducted to identify genes that exhibited differential expression in glioma cells treated with scoparone compared to untreated cells. Subsequently, the impact of scoparone on the proliferation, migration, and invasion of glioma cells was assessed in vitro using a range of assays including cell viability, colony formation, wound healing, and transwell assays. Moreover, the apoptotic effects of scoparone on glioma cells were evaluated through flow cytometry and western blot analysis. Furthermore, we established a glioma xenograft mouse model to assess the in vivo antitumor activity of scoparone. Lastly, by integrating transcriptome analysis, we endeavored to unravel the molecular mechanisms underlying the observed antitumor effects of scoparone by examining the expression levels of RhoA/ROCK1 signaling pathway components using western blot analysis and qRT-PCR. RESULTS: Our transcriptome sequencing results revealed that scoparone significantly downregulated RhoA/ROCK1 signaling in glioma cells. Furthermore, scoparone treatment inhibited glioma cell proliferation, migration, and invasion, and promoted cell apoptosis in vitro. Moreover, scoparone reduced tumor growth and prolonged survival in a glioma xenograft mouse model, and improved the toxicity of temozolomide. Finally, our results showed that the antitumor effects of scoparone were mediated by the suppression of RhoA/ROCK1 signaling. CONCLUSION: Scoparone could be a promising therapeutic agent for glioma by suppressing RhoA/ROCK1 signaling. These findings pave the way for future research endeavors aimed at the development and optimization of scoparone-based therapeutic strategies.

Nomogram based on CMTM6 expression and clinical characteristics to predict postoperative overall survival in patients with hepatocellular carcinoma.

BACKGROUND: The purpose of this study was to investigate the expression of CMTM6 in HCC tissues and its prognostic value, and to try to develop a nomogram prognostic model based on CMTM6. METHODS: In this retrospective study, immunohistochemical (IHC) staining was performed in 178 patients who underwent radical hepatectomy in the same surgical team. R software was used to construct the nomogram model. The Bootstrap sampling method was used for internal validation. RESULTS: CMTM6 is significantly expressed in HCC tissues and is closely associated with decreased overall survival (OS). PVTT (HR = 6.2, 95% CI: 3.06 12.6, P<0.001), CMTM6 (HR=2.30, 95% CI: 1.27 4.0, P=0.006) and MVI (HR=10.8, 95% CI: 4.19-27.6, P<0.001) were independent predictors of OS. The nomogram combined with CMTM6, PVTT and MVI was more predictive than the traditional TNM scoring system, and the prediction effects of 1-year and 3-year OS were accurate. CONCLUSIONS: The prognosis of a patient may be predicted using high levels of CMTM6 expression in HCC tissues, and the nomogram model including CMTM6 expression has the best predictive ability.

Akkermansia muciniphila protects the intestine from irradiation-induced injury by secretion of propionic acid.

Intestinal dysbiosis frequently occurs in abdominal radiotherapy and contributes to irradiation (IR)-induced intestinal damage and inflammation. Akkermansia muciniphila (A. muciniphila) is a recently characterized probiotic, which is critical for maintaining the dynamics of the intestinal mucus layer and preserving intestinal microbiota homeostasis. However, the role of A. muciniphila in the alleviation of radiation enteritis remains unknown. In this study, we reported that the abundance of A. muciniphila was markedly reduced in the intestines of mice exposed to abdominal IR and in the feces of patients who received abdominal radiotherapy. Abundance of A. muciniphila in feces of radiotherapy patients was negatively correlated with the duration of diarrhea in patients. Administration of A. muciniphila substantially mitigated IR-induced intestinal damage and prevented mouse death. Analyzing the metabolic products of A. muciniphila revealed that propionic acid, a short-chain fatty acid secreted by the microbe, mediated the radioprotective effect. We further demonstrated that propionic acid bound to G-protein coupled receptor 43 (GRP43) on the surface of intestinal epithelia and increased histone acetylation and hence enhanced the expression of tight junction proteins occludin and ZO-1 and elevated the level of mucins, leading to enhanced integrity of intestinal epithelial barrier and reduced radiation-induced intestinal damage. Metformin, a first-line agent for the treatment of type II diabetes, promoted intestinal epithelial barrier integrity and reduced radiation intestinal damage through increasing the abundance of A. muciniphila. Together, our results demonstrated that A. muciniphila plays a critical role in the reduction of abdominal IR-induced intestinal damage. Application of probiotics or their regulators, such as metformin, could be an effective treatment for the protection of radiation exposure-damaged intestine.

Stimulated thyroglobulin and pre-ablation antithyroglobulin antibody products can predict the response to radioiodine therapy of TgAb-positive differentiated thyroid cancer patients: a retrospective study.

Objective: We aimed to explore the predictive value of stimulated thyroglobulin (sTg) and pre-ablation antithyroglobulin (pa-TgAb) products for the effect of radioiodine therapy (RAIT) on TgAb-positive differentiated thyroid cancer (DTC) patients. Methods: In this study, we enrolled 265 patients with TgAb-positive DTC who underwent RAIT after total thyroidectomy (TT). Based on the last follow-up result, the patients were divided into two groups: the excellent response (ER) group and the non-excellent response (NER) group. We analyzed the factors related to the effect of RAIT. Results: The ER group consisted of 197 patients. The NER group consisted of 68 patients. For the univariate analysis, we found that the maximal tumor diameter, whether with extrathyroidal extension (ETE), bilateral or unilateral primary lesion, multifocality, preoperative TgAb (preop-TgAb), pa-TgAb, sTg × pa-TgAb, initial RAIT dose, N stage, and surgical extent (modified radical neck dissection or not), showed significant differences between the ER group and NER group (all p-values <0.05). The receiver operating characteristic (ROC) curves showed that the cutoff value was 724.25 IU/ml, 424.00 IU/ml, and 59.73 for preop-TgAb, pa-TgAb, and sTg × pa-TgAb, respectively. The multivariate logistic regression analysis results indicated that pa-TgAb, sTg × pa-TgAb, initial RAIT dose, and N stage were independent risk factors for NER (all p-values <0.05). For the Kaplan-Meier analysis of disease-free survival (DFS), the median DFS of the patients with sTg × pa-TgAb < 59.73 and initial RAIT dose ≤ 100 mCi was significantly longer than that of the patients with sTg × pa-TgAb ≥ 59.73 (50.27 months vs. 48.59 months, p = 0.041) and initial RAIT dose >100 mCi (50.50 months vs. 38.00 months, p = 0.030). Conclusion: We found the sTg and pa-TgAb conducts is a good predictor of the efficacy of RAIT in TgAb-positive DTC patients. It can play a very positive and important role in optimizing treatment, improving prognosis, and reducing the burden of patients.

Programming Affinity for Precise Tumor Recognition with Allosteric Nanosensing-Circles.

Although many smart probes for precise tumor recognition have been reported, the challenge of "on-target, off-tumor" remains. Therefore, we herein report the fabrication of a series of allosterically tunable DNA nanosensing-circles (NSCs). The recognition affinity of NSCs is programmed through sensitivity to tumor microenvironment (TME) hallmarks such as small molecules, acidity, or oncoproteins. Because of their special programming conditions and active targeting capabilities, NSCs can overcome the obstacles noted above, thus achieving precise tumor recognition. Results from in vitro analysis demonstrated that NSCs obtain their recognition ability through allosteric regulation after sensing TME hallmarks. Furthermore, in vivo imaging indicated that NSCs enable precise tumor imaging. These results demonstrate that our NSCs will be promising tools for precise tumor imaging and therapy.

[Retracted] Deoxypodophyllotoxin inhibits cell viability and invasion by blocking the PI3K/Akt signaling pathway in human glioblastoma cells.

Following the publication of the above article and a corrigendum that was published to address issues of duplicated data panels in Fig. 4 (doi: 10.3892/or.2023.8484), a concerned reader has drawn to the Editor's attention that Fig. 3B also contains a matching pair of identical flow cytometry scatterplots where the results from different experiments were intended to have been portrayed, and certain of the western blotting data shown in Fig. 3C are strikingly similar to data that had appeared in Figs. 2 and 3 in a previously published paper written by different authors at different research institutes [Tian F, Ding D and Li D: Fangchinoline targets PI3K and suppresses PI3K/AKT signaling pathway in SGC7901 cells. Int J Oncol 46: 2355­2363, 2015]. In view of the fact that certain of the data in the above article had already appeared in a previously published paper, and given the large number of apparently overlapping data panels identified in several of the figures, the Editor of Oncology Reports has decided that this paper should be retracted from the publication. After having been in contact with the authors, they accepted the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 41: 2453­2463, 2019; DOI: 10.3892/or.2019.7016].

Molecular mechanisms of snoRNA-IL-15 crosstalk in adipocyte lipolysis and NK cell rejuvenation.

Obesity, in which the functional importance of small nucleolar RNAs (snoRNAs) remains elusive, correlates with risk for many cancer types. Here, we identify that the serum copies of adipocyte-expressed SNORD46 correlate with body mass index (BMI), and serum SNORD46 antagonizes interleukin-15 (IL-15) signaling. Mechanically, SNORD46 binds IL-15 via G11, and G11A (a mutation that significantly enhances binding affinity) knockin drives obesity in mice. Functionally, SNORD46 blocks IL-15-induced, FER kinase-dependent phosphorylation of platelet glycoprotein 4 (CD36) and monoglyceride lipase (MGLL) in adipocytes, leading to inhibited lipolysis and browning. In natural killer (NK) cells, SNORD46 suppresses the IL-15-dependent autophagy, leading to reduced viability of obese NK. SNORD46 power inhibitors exhibit anti-obesity effects, concurring with improved viability of obese NK and anti-tumor immunity of CAR-NK cell therapy. Hence, our findings demonstrate the functional importance of snoRNAs in obesity and the utility of snoRNA power inhibitors for antagonizing obesity-associated immune resistance.

[Retracted] miR­489 promotes apoptosis and inhibits invasiveness of glioma cells by targeting PAK5/RAF1 signaling pathways.

Subsequently to the publication of the article, an interested reader drew to the authors' attention that certain of the data panels showing the results of cell migration and invasion assays in Figs. 5A and 6C were overlapping, suggesting that the data were derived from the same original source, even though they were selected to represent the results from differently performed experiments. The authors requested that a corrigendum be published to rectify this problem; however, after having conducted an independent analysis of the data in the Editorial Office, we have noticed that the data shown in Figs. 5A and 6C are strikingly similar to data appearing in different form in other articles published in another journal, mainly written by different authors at different research institutions. Owing to the fact that the contentious data in the above article were already under consideration for publication, or had already been published, elsewhere at the time it was submitted to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 42: 2390­2401, 2019; DOI: 10.3892/or.2019.7381].

Experiments and machine learning-based modeling for haloacetic acids rejection by nanofiltration: Influence of solute properties and operating conditions.

Because of potential risks to public health, the presence of haloacetic acids (HAAs) in drinking water is a major concern. Nanofiltration (NF) has shown potential for HAAs rejection, and several factors, namely, membrane properties, solute properties, and operating conditions, have been revealed key roles. However, knowledge of NF separation mechanism by quantifying these factors is limited. This study investigated and modeled NF performance on HAAs rejection. NF performance was experimentally investigated under various transmembrane pressure (TMP), cross-flow velocity (CV), temperature, pH, ionic strength (IS), and HAAs initial feed concentration (Cin). We used machine learning (ML) to understand the mechanism from the perspective of HAAs properties and operating conditions. Multiple linear regression (MLR), support vector machine (SVM), multsilayer perceptron (MLP), extreme gradient boosting (XGBoost), and random forest (RF) models were used. The MLP, XGBoost and RF models achieved significant performance with high R2 (0.970, 0.973, and 0.980) and low RMSE (4.71, 4.41, and 3.84). These three models were analyzed using the Shapley Additive explanation (SHAP) to quantify relative contributions of HAAs properties and operating conditions. XGBoost-SHAP produced the most logical results and was the best-performing model for selecting optimal input variables combinations. The results showed that Stokes radius (rs), logarithmic octanol-water partitioning coefficient (logKow), molecular weight (MW), pH, TMP, and temperature are key variables for interpreting NF process. The effects of HAAs properties were ranked as rs > logKow > MW, suggesting significance of size exclusion and hydrophobic interaction. The impact of the operational conditions followed the order pH > TMP > temperature, illustrating that pH was the major influencing operating condition. This study demonstrated significant capacity of ML, which reduced amount of experimental work. In addition, the main operating conditions can be evaluated in terms of their contributions, making ML an efficient tool for risk management and process optimization.

LIFR recruits HGF-producing neutrophils to promote liver injury repair and regeneration.

The molecular links between tissue repair and tumorigenesis remain elusive. Here, we report that loss of the liver tumor suppressor Lifr in mouse hepatocytes impairs the recruitment and activity of reparative neutrophils, resulting in the inhibition of liver regeneration after partial hepatectomy or toxic injuries. On the other hand, overexpression of LIFR promotes liver repair and regeneration after injury. Interestingly, LIFR deficiency or overexpression does not affect hepatocyte proliferation ex vivo or in vitro . In response to physical or chemical damage to the liver, LIFR from hepatocytes promotes the secretion of the neutrophil chemoattractant CXCL1 (which binds CXCR2 to recruit neutrophils) and cholesterol in a STAT3-dependent manner. Cholesterol, in turn, acts on the recruited neutrophils to secrete hepatocyte growth factor (HGF) to accelerate hepatocyte proliferation and regeneration. Altogether, our findings reveal a LIFR-STAT3- CXCL1-CXCR2 axis and a LIFR-STAT3-cholesterol-HGF axis that mediate hepatic damage- induced crosstalk between hepatocytes and neutrophils to repair and regenerate the liver.

Efficacy evaluation and influencing factor analysis of postoperative 131I for the treatment of primary hyperthyroidism combined with differentiated thyroid cancer (DTC)-a retrospective cohort study.

Background: 131I treatment is one of the important methods of comprehensive postoperative treatment for patients with hyperthyroidism complicated with differentiated thyroid cancer (DTC). Early identification of patients with poor treatment efficacy of 131I is particularly important. Current studies mainly focus on the relationship between hyperthyroidism and the occurrence and development of DTC, and there are few studies on the factors affecting the curative effect. The purpose of this study was to find the influencing factors of efficacy evaluation and provide evidence for early identification of patients with poor efficacy in DTC combined with primary hyperthyroidism patients. Methods: This was a retrospective analysis of DTC patients with primary hyperthyroidism who received 131I treatment in our department from 2012 to 2021. Follow-up intervals were 3 months within 1 year, 6 months within 1 to 2 years, and annual follow-up thereafter, the median follow-up time was 12.0 (3.0, 24.0) months. Serological examination and imaging examination were used to evaluate the efficacy. Patients were classified into an excellent response (ER) group and a non-ER group based on treatment response more than 6 months after 131I treatment. Univariate analysis and multivariate logistic regression analysis were performed on the basic clinical characteristics, pathological characteristics and curative effect of the patients, in order to find independent risk factors affecting the curative effect. Results: Eighty-nine patients were mostly female (80.9%), the average age was 43.47±11.88 years old, and tumor size was 1.2 (0.75, 1.80) cm, 56 patients (62.9%) in the ER group. psTg [odds ratio (OR): 1.325; 95% confidence interval (CI): 1.135-1.547; P<0.001], maximum tumor diameter (OR: 2.428; 95% CI: 1.392-4.235; P=0.002) and pathology-confirmed combined HT (OR: 8.669; 95% CI: 1.877-40.038; P=0.006) were independent risk factors for predicting ER. Conclusions: Our findings demonstrate that most hyperthyroidism combined with DTC patients could get favorable clinical outcomes from 131I treatment. The tumor diameter, pathology-confirmed diagnosis of combined HT, and psTg level can be used to identify patients who can get ER by the effect of 131I in hyperthyroidism combined with DTC at an early stage.

Tumor-associated nonmyelinating Schwann cell-expressed PVT1 promotes pancreatic cancer kynurenine pathway and tumor immune exclusion.

One of the major obstacles to treating pancreatic ductal adenocarcinoma (PDAC) is its immunoresistant microenvironment. The functional importance and molecular mechanisms of Schwann cells in PDAC remains largely elusive. We characterized the gene signature of tumor-associated nonmyelinating Schwann cells (TASc) in PDAC and indicated that the abundance of TASc was correlated with immune suppressive tumor microenvironment and the unfavorable outcome of patients with PDAC. Depletion of pancreatic-specific TASc promoted the tumorigenesis of PDAC tumors. TASc-expressed long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) was triggered by the tumor cell-produced interleukin-6. Mechanistically, PVT1 modulated RAF proto-oncogene serine/threonine protein kinase-mediated phosphorylation of tryptophan 2,3-dioxygenase in TASc, facilitating its enzymatic activities in catalysis of tryptophan to kynurenine. Depletion of TASc-expressed PVT1 suppressed PDAC tumor growth. Furthermore, depletion of TASc using a small-molecule inhibitor effectively sensitized PDAC to immunotherapy, signifying the important roles of TASc in PDAC immune resistance.

Prediction of outcomes for symptomatic spinal cavernous malformation surgery: a multicenter prospective clinical study.

PURPOSE: Clinical outcome of spinal cavernous malformation (SCM) varies because of its unclear natural history, and reliable prognostic prediction model for SCM patients is limited. The aim of the present study was to investigate potential factors that predict one-year neurological status in postoperative patients with SCM. METHODS: This was a multicenter prospective observational study in consecutive patients with SCMs. SCMs treated microsurgically between January 2015 and January 2021 were included. Outcome was defined as the American Spinal Injury Association Impairment Scale (AIS) grade at one year after operation. Multivariable analyses were used to construct the best predictive model for patient outcomes. RESULTS: We identified 268 eligible SCM patients. Neurological outcome had worsened from preoperative baseline in 51 patients (19.0%) at one year. In the multivariable logistic regression, the best predictive model for unfavorable outcome included symptom duration ≥ 26 months (95% CI 2.80-16.96, P < 0.001), size ≤ 5 mm (95% CI 1.43-13.50, P = 0.010), complete intramedullary (95% CI 1.69-8.14, P = 0.001), subarachnoid hemorrhage (95% CI 2.92-12.57, P < 0.001), AIS B (95% CI 1.91-40.93, P = 0.005) and AIS C (95% CI 1.12-14.54, P = 0.033). CONCLUSIONS: Admission size of the lesion, morphology, symptom duration, AIS grade and the presence of subarachnoid hemorrhage were strong outcome predictors regarding prognostication of neurological outcome in postoperative patients with SCMs. A decision to surgically remove a symptomatic SCM should be justified by systematic analysis of all factors potentially affecting outcome.

[Corrigendum] Deoxypodophyllotoxin inhibits cell viability and invasion by blocking the PI3K/Akt signaling pathway in human glioblastoma cells.

Following the publication of the above article, a concerned reader drew to the authors' attention that various pairs of the data panels shown for the Transwell migration assays in Fig. 4A­D on p. 2459 featured overlapping data, such that a number of the panels may have been derived from the same original sources. The authors have examined their original data, and realize that errors were inadvertently made during the assembly of these figure parts. The authors have reassembled Fig. 4 containing alternative data in Fig. 4A­D, and the revised version of this figure is shown on the next page. Note that the revised data shown for this figure do not affect the overall conclusions reported in the paper. All the authors agree with the publication of this corrigendum, and are grateful to the Editor of 1 for allowing them the opportunity to publish this. They also apologize to the readership for any inconvenience caused. [Oncology Reports 41: 2453­2463, 2019; DOI: 10.3892/or.2019.7016].

Aptamer Inhibits Tumor Growth by Leveraging Cellular Proteasomal Degradation System to Degrade c-Met in Mice.

Current action mechanisms for aptamer-based therapeutics depend on occupancy-driven pharmacology to mediate protein functions. We report a new mechanism where aptamers leverage cellular proteasomal degradation system to degrade proteins for cancer treatment. A DNA aptamer (hereinafter referred to as c-Met-Ap) binds to the extracellular domain of mesenchymal-epithelial transition factor (c-Met) and selectively induces c-Met phosphorylation at Y1003 and Y1349. The phosphorylation of Y1003 recruits E3 ubiquitin ligase casitas B-lineage lymphoma, causing c-Met ubiquitination and degradation in the proteasome. Furthermore, c-Met-Ap can induce a decrease in the heterodimeric partner proteins of c-Met and the downstream effector proteins in the c-Met signal axis, effectively inhibiting tumor growth in A549 tumor-bearing BALB/c mice. Our study uncovers a novel, actionable mechanism for aptamer therapeutics and opens a new avenue for developing highly efficient anticancer drugs.

Bispecific Aptamer-Based Recognition-then-Conjugation Strategy for PD1/PDL1 Axis Blockade and Enhanced Immunotherapy.

Cytotoxic T cells initiate antitumor effects mainly through direct interactions with tumor cells. As a counter to this, tumor cells can put the brakes on such T-cell activity via specific linkage between programmed death ligand 1 (PDL1) and its receptor programmed cell death protein 1 (PD1). Bispecific inhibitors that enabled synchronous blockade of PD1 and PDL1, thereby releasing the brakes on T-cell antitumor activity, should significantly improve the efficacy of immune checkpoint blockade (ICB) therapy. In this work, we identified a DNA aptamer, Ap3, that could specifically recognize PDL1 on tumor cells and competed with the binding of PD1. By integrating Ap3 with an anti-PD1 aptamer, the bispecific aptamer Ap3-7c was constructed, and it showed promise for improving the T-cell immune response. We further designed a dibenzocyclooctyne (DBCO)-labeled bispecific aptamer, D-Ap3-7c, allowing covalent conjugation of aptamers onto PD1 and PDL1 after specific cell recognition. Our in vivo studies showed that this recognition-then-conjugation strategy could induce a potent immunological effect against tumors. This work is expected to provide clues for antitumor immunotherapy.