ALDH1A1 promotes immune escape of tumor cells through ZBTB7B-glycolysis pathway.

The primary impediment to the success of immunotherapy lies in the immune evasion orchestrated by tumors, contributing to the suboptimal overall response rates observed. Despite this recognition, the intricacies of the underlying mechanisms remain incompletely understood. Through preliminary detection of clinical patient tissues, we have found that ALDH1A1 was a key gene for the prognosis of cancer patients and tumor glycolysis. In vitro experiments and tumor formation in nude mice suggested that targeting ALDH1A1 could inhibit tumor growth. Through further analysis of xenograft tumor models in immune-normal mice and flow cytometry, we found that deficiency in ALDH1A1 could promote immune system suppression of tumors in vivo. Specifically, RNA-seq analysis, combined with qPCR and western blot, identified the transcription factor ZBTB7B as downstream of ALDH1A1. The binding sites of the transcription factor ZBTB7B on the LDHA promoter region, which is responsible for regulating the rate-limiting enzyme gene LDHA in glycolysis, were determined using luciferase reporter gene detection and Chip-qPCR, respectively. In addition, the increased SUMOylation of ZBTB7B stabilized its transcriptional activity. Further in vivo and in vitro experiments confirmed that the combination of targeting ALDH1A1 and ZBTB7B with immune checkpoint inhibitors could synergistically inhibit tumors in vivo. Finally, after conducting additional verification of patient tissue and clinical data, we have confirmed the potential translational value of targeting ALDH1A1 and ZBTB7B for tumor immunotherapy. These results emphasize the potential translational significance of targeting ALDH1A1 and ZBTB7B in the realm of tumor immunotherapy. The convergence of ALDH1A1 inhibition and immune checkpoint blockade, particularly with PD-L1/PD-1 mAb, presents a compelling avenue for curtailing tumor immune escape.

Evaluating PAX1 methylation for cervical cancer screening triage in non-16/18 hrHPV-positive women.

BACKGROUND: In China, the national cervical cancer screening protocol involves initial testing for high-risk human papillomavirus (hrHPV), followed by cytology for hrHPV-positive cases. This study evaluates the effectiveness of PAX1 methylation (PAX1m) analysis in identifying precancerous or cancerous lesions in cervical samples from Chinese women positive for non-16/18 hrHPV strains. METHODS: Between February 2022 and March 2023, 281 cervical samples from non-16/18 hrHPV-positive women underwent cytological examination and PAX1m analysis. The study assessed the statistical relationship between PAX1m levels and the presence of cervical lesions, comparing the diagnostic performance of PAX1m to conventional cytology. RESULTS: A significant association was found between PAX1 methylation levels and the risk of CIN2 + and CIN3 + lesions, with 47 instances of CIN2 + detected. Odds ratios (ORs) for moderate and high PAX1m levels were 8.86 (95% CI: 2.24-42.17) and 166.32 (95% CI: 47.09-784.97), respectively. The area under the ROC curve for PAX1m in identifying CIN2 + lesions was 0.948 (95% CI: 0.895-0.99). PAX1m demonstrated similar sensitivity and negative predictive value (NPV) to cytology but reduced the colposcopy referral rate from 47.7% with cytology alone to 25.6% with PAX1m, showing superior specificity and positive predictive value across age groups. CONCLUSIONS: PAX1 methylation is a strong indicator of CIN2 + and CIN3 + risk, offering diagnostic performance comparable to cytology with the added benefit of reduced unnecessary colposcopy referrals. These findings support the use of PAX1m analysis as a reliable tool for triaging non-16/18 hrHPV-positive women in outpatient settings.

Central imaging based on near-infrared functional imaging technology can be useful to plan management in patients with chronic lateral ankle instability.

BACKGROUND: Near infrared brain functional imaging (FNIRS) has been used for the evaluation of brain functional areas, the imaging differences of central activation of cognitive-motor dual tasks between patients with chronic lateral ankle instability (CLAI) and healthy population remain unclear. This study aimed to evaluated the role of central imaging based on FNIRS technology on the plan management in patients with CLAI, to provide insights to the clinical treatment of CLAI. METHODS: CLAI patients treated in our hospital from January 1, 2021 to June 31, 2022 were selected. Both CLAI patients and health controls were intervened with simple task and cognitive-motor dual task under sitting and walking conditions, and the changes of oxygenated hemoglobin concentration in bilateral prefrontal cortex (PFC), premotor cortex (PMC) and auxiliary motor area (SMA) were collected and compared. RESULTS: A total of 23 participants were enrolled. There were significant differences in the fNIRS ΔHbO2 of barefoot subtractive walking PFC-R and barefoot subtractive walking SMA-R between experimental and control group (all P < 0.05). There was no significant difference in ΔHbO2 between the experimental group and the control group in other states (P > 0.05). There was no significant difference in ΔHbO2 between the experimental group and the control group in each state of the brain PMC region. CONCLUSION: Adaptive alterations may occur within the relevant brain functional regions of individuals with CLAI. The differential activation observed between the PFC and the SMA could represent a compensatory mechanism emerging from proprioceptive afferent disruptions following an initial ankle sprain.

A systematic review and meta-analysis of balance training in patients with chronic ankle instability.

BACKGROUND: Chronic ankle instability (CAI) is a common yet serious problem for elder patients. This meta-analysis aimed to evaluate the effects of balance training for CAI, to provide evidence for the clinical treatment, and care of CAI patients. METHODS: Two investigators searched PubMed, EMBASE, Science Direct, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Wanfang, and Weipu Databases up to May 20, 2023, for randomized controlled trials (RCTs) on the effects of balance training for CAI. The mean difference (MD) with 95% confidence intervals (95%CIs) was calculated for each outcome with a fixed or random effect model. Review Manager 5.3 software was used for meta-analysis. RESULTS: Nine RCTs involving 341 patients were included. Meta-analysis results showed that compared with blank controls, balanced training treatment of CAI could significantly improve the score of CAI [MD = 3.95, 95% CI (3.26, 4.64), P < 0.00001], SEBT-PM [MD = 4.94, 95% CI (1.88, 8.00), P = 0.002], SEBT-PL [MD = 5.19, 95% CI (1.57, 8.81), P = 0.005], and FAAM Sports [MD = 17.74, 95% CI (14.36, 21.11), P < 0.00001]. Compared with strength training, balance training treatment of CAI improved the score of CAIT [MD = 2.36, 95% CI (0.29, 4.44), P = 0.03], FAAM-ADL [MD = 4.06, 95% CI (1.30, 6.83), P = 0.004]. CONCLUSION: The analysis outcomes indicate that balance training enhances daily activity capability, motor function, and dynamic balance to different extents. Additionally, when comparing the results of balance training and strength training, no significant difference was observed between the two methods in improving the dynamic stability of CAI patients. However, it is noteworthy that balance training exhibits a more pronounced impact on enhancing functional scale scores.

Effect of L-carnitine in Ameliorating Lipopolysaccharide-Induced Cardiomyocyte Injury via MAPK Signaling.

The present study aimed to elucidate whether L-carnitine (LC) protected H9c2 cells and its underlying mechanisms. Cell counting kit-8 (CCK-8) assay was used to evaluate cell viability. Apoptosis, cell morphology, and lactate dehydrogenase (LDH) assessment were used to prove effects of lipopolysaccharide (LPS) and LC on H9c2 cells. RT-qPCR and western blot assays were hired to evaluate the mRNA and protein expression levels, respectively. ELISA assay was performed to determine the released protein levels. Reactive oxygen species (ROS) level was evaluated by immunofluorescence and flow cytometry. LC was revealed to protect H9c2 cells against LPS-induced injury as indicated by increased cell viability, reduced apoptosis ratio and LDH level. LC treatment also reduced BAX expression as well as up-regulated Bcl-2 expression under LPS treatment. Mechanically, LC reduced oxidative stress and ameliorated the mitochondrial injury through modulating extracellular signal-regulated kinase 1/2 and c-Jun N-terminal protein kinase c-Jun N-terminal protein kinase phosphorylation levels as indicated by decreased membrane potential, increased ATP production and mtDNA expression. We found that LC ameliorates LPS-induced cardiomyocyte injury by abrogating cell apoptosis ratio, ROS levels, as well as mitochondrial dysfunction via mitogen-activated protein kinase signaling. Our findings revealed a potential drug for sepsis or LPS-induced cardiomyocyte injury.

The Diagnosis Significance of Serum Cysteine Protease Inhibitors (CST4) in Colorectal Cancer.

OBJECTIVE: This study aims to evaluate the diagnostic value of human serum cysteine protease inhibitors (cystatin 4 [CST4]) in colorectal cancer (CRC) patients. METHODS: A total of 291 patients who were admitted to Zhuzhou Central Hospital for colonoscopy from January 2020 to December 2021 and met the inclusion criteria were selected. Serum samples of the patients were collected, and CST4 was detected by double-antibody sandwich enzyme-linked immunosorbent assay. Simultaneously, CEA and CA19-9 were detected, and the patients were divided into the CRC group, benign lesion group, and healthy control group. An attempt was made to construct a CRC prediction model including CST4 and draw a subject working characteristic curve as a diagnostic threshold for CRC prediction, and evaluate the diagnostic efficacy of the above indicators. At the same time, the expression analysis of CST4, CEA, and CA19-9 was verified by combining the data of CRC in the Tumor Genome Atlas (TCGA). RESULTS: In this study, the levels of serum CST4, CEA, and CA19-9 in the CRC group were higher than those in the colorectal benign lesion group and healthy control group, with statistical significance (P < .001). The analysis results of the receiver operating characteristic curve showed that the area under the receiver operator characteristic curve (AUC) of CST4 was 0.7739, which was obviously larger than the AUC of CA19-9 and CEA. CRC data from the TCGA expression database showed that CST4 expression and CEA expression were higher in CRC patients than in normal samples. The combined model based on CST4 was successfully constructed, and the AUC for predicting the occurrence of CRC was 0.7851. CONCLUSION: CST4 is a novel and improved diagnostic marker for CRC. The combined model based on CST4 has a certain potential value in terms of predicting the occurrence of intestinal cancer.

ACADL suppresses PD-L1 expression to prevent cancer immune evasion by targeting Hippo/YAP signaling in lung adenocarcinoma.

Lung cancer is the leading cause of cancer-related death. Cancer immune evasion is a key barrier in the treatment of lung cancer and the development of effective anticancer therapeutics. Long-chain Acyl-CoA dehydrogenase (ACADL), a key enzyme that regulates ß-oxidation of long-chain fatty acyl-CoAs, has been found to act as a tumor suppressor in cancers. However, the role of ACADL in lung adenocarcinoma (LUAD) has not been explored. In the current study, we find that ACADL functions as a tumor suppressor in LUAD to inhibit proliferation and enhanced chemotherapeutic drug-induced apoptosis. Interestingly, ACADL prevents tumor immune evasion by suppressing PD-L1 expression in LUAD. ACADL is critical for Hippo/YAP pathway-mediated PD-L1 regulation. Moreover, YAP activation is essential for ACADL suppression of PD-L1 transcription. In addition, ACADL increases the protein stability and kinase activity of LATS kinase to inhibit YAP activation and PD-L1 transcription. Furthermore, we show that ACADL expression is positively correlated with a better OS and FP in LUAD. Our data reveals that ACADL could be a promising target for regulating Hippo/YAP pathway to prevent tumor immune evasion in LUAD.

RHOA G17V induces T follicular helper cell specification and involves angioimmunoblastic T-cell lymphoma via upregulating the expression of PON2 through an NF-κB-dependent mechanism.

Angioimmunoblastic T-cell lymphoma (AITL) is a malignant hematologic tumor arising from T follicular helper (Tfh) cells. High-throughput genomic sequencing studies have shown that AITL is characterized by a novel highly recurring somatic mutation in RHOA, encoding p.Gly17Val (RHOA G17V). However, the specific role of RHOA G17V in AITL remains unknown. Here, we demonstrated that expression of Rhoa G17V in CD4+ T cells increased cell proliferation and induces Tfh cell specification associated with Pon2 upregulation through an NF-κB-dependent mechanism. Further, loss of Pon2 attenuated oncogenic function induced by genetic lesions in Rhoa. In addition, an abnormality of RHOA G17V mutation and PON2 expression is also detected in patients with AITL. Our findings suggest that PON2 associated with RHOA G17V mutation might control the direction of the molecular agents-based AITL and provide a new therapeutic target in AITL.

NDR1 activates CD47 transcription by increasing protein stability and nuclear location of ASCL1 to enhance cancer stem cell properties and evasion of phagocytosis in small cell lung cancer.

Small cell lung cancer (SCLC) is one of the most malignant types of lung cancer. Cancer stem cell (CSC) and tumor immune evasion are critical for the development of SCLC. We previously reported that NDR1 enhances breast CSC properties. NDR1 might also have a role in the regulation of immune responses. In the current study, we explore the function of NDR1 in the control of CSC properties and evasion of phagocytosis in SCLC. We find that NDR1 enhances the enrichment of the ALDEFLUORhigh and CD133high population, and promotes sphere formation in SCLC cells. Additionally, NDR1 upregulates CD47 expression to enhance evasion of phagocytosis in SCLC. Furthermore, the effects of NDR1 enhanced CD47 expression and evasion of phagocytosis are more prominent in CSC than in non-CSC. Importantly, NDR1 promotes ASCL1 expression to enhance NDR1-promoted CSC properties and evasion of phagocytosis in SCLC cells. Mechanically, NDR1 enhances protein stability and the nuclear location of ASCL1 to activate the transcription of CD47 in SCLC. Finally, CD47-blocking antibody can be used to target NDR1 enhanced CSC properties and evasion of phagocytosis by suppressing EGFR activation in SCLC. In summary, our data indicate that NDR1 could be a critical factor for modulating CSC properties and phagocytosis in SCLC.

Identification of Gefitinib Resistance-Related lncRNA-miRNA-mRNA Regulatory Networks and Corresponding Prognostic Signature in Patients with Lung Adenocarcinoma.

Purpose: To identify and characterize gefitinib resistance-related (GefR-related) lncRNAs and construct a prediction model for lung adenocarcinoma (LUAD). Methods: Differential expression analysis between PC9 and gefitinib-resistant PC9 (PC9GR) cell samples was performed to screen GefR-related lncRNAs and mRNAs based on the GSE34228 dataset. These lncRNAs, mRNAs, and their corresponding microRNAs (miRNAs) were used to construct the GefR-related network and PPI networks. Functional enrichment analyses were conducted using the STRING database. A prognostic signature was developed using the TCGA dataset. The reliability of the signature was tested using the Kaplan-Meier method and ROC curve. Lastly, the FZD4-associated ceRNA subnetwork was selected to confirm the in vitro expressions of the GefR-related lncRNAs using RT-qPCR assay. Results: A GefR-related ceRNA network that consists of 35 miRNAs, 26 lncRNAs, and 179 mRNAs was constructed. Then, 20 hub genes were screened from the targeted mRNAs of the constructed PPI network, and enrichment analysis identified relevant enriched pathways. We also constructed a prognostic signature for LUAD based on nine mRNAs in the GefR-related ceRNA network. The 9-mRNA signature was an independent predictor of LUAD, the AUC produced by ROC analysis showed a good predictive power of the model, and Kaplan-Meier analysis showed poorer outcomes in the high-risk group, relative to the low-risk group. Lastly, MIR137HG and ZNF295-AS1 levels were found to be associated with gefitinib resistance and exerted their functions through the ceRNA mechanism. Conclusion: We established a prognostic signature and identified two lncRNAs (MIR137HG and ZNF295-AS1) with potential significant roles in gefitinib resistance.

NKX6-1 Is a Less Sensitive But Specific Biomarker of Chromophobe Renal Cell Carcinoma.

NKX6-1 is a transcription factor that plays a key role in the development, differentiation, and identity maintenance of beta cells of pancreatic islets. Although NKX6-1 expression has also been discovered in pancreatic well-differentiated neuroendocrine tumors (WDNETs) and duodenal WDNETs, its expression in chromophobe renal cell carcinoma (chRCC) is unexplored. Analysis of mRNA expression and immunohistochemistry of NKX6-1 was performed using the kidney cancer cohort from The Cancer Genome Atlas (TCGA) and paraffin-embedded whole-tissue slides from our 196 collected cases, including 48 chRCCs (43 classic and 5 eosinophilic subtypes), 24 renal oncocytomas (ROs), 46 clear cell renal cell carcinomas, 41 papillary renal cell carcinomas, 14 renal urothelial carcinomas, 7 low-grade oncocytic renal tumors (LOTs), 8 eosinophilic solid and cystic renal cell carcinomas, 3 succinate dehydrogenase-deficient renal cell carcinomas, and 5 renal oncocytic tumors, not otherwise specified. NKX6-1 expression was almost exclusively upregulated in chRCC at both the mRNA and protein levels compared with other renal tumors. NKX6-1 was immunohistochemically positive in 39 of 48 (81.3%) chRCCs, but negative in 46 clear cell renal cell carcinomas, 24 ROs, 7 low-grade oncocytic renal tumors, 8 eosinophilic solid and cystic renal cell carcinomas, 3 succinate dehydrogenase-deficient renal cell carcinomas, and 5 renal oncocytic tumors, not otherwise specified. Diffuse, moderate, and focal NKX6-1 staining were seen in 21, 4, and 14 of the 39 chRCCs, respectively. In contrast, NKX6-1 was focally positive in only 1 of 41 (2.4%) papillary renal cell carcinomas and 2 of 14 (14.3%) renal urothelial carcinomas. Therefore, the sensitivity and specificity of NKX6-1 staining were 81.3% and 98% for chRCC, respectively. In conclusion, NKX6-1 may be a novel potential marker for differentiating chRCC from other renal neoplasms, especially from RO.

Intestinal intussusception caused by intestinal duplication and ectopic pancreas: A case report and review of literature.

BACKGROUND: Intestinal intussusception caused by intestinal duplication and ectopic pancreas is extremely rare in the clinic and has not been reported previously. CASE SUMMARY: A 29-year-old man was admitted to the hospital for chronic abdominal pain and bloating. The preoperative diagnosis was intestinal obstruction and intussusception. Then, laparotomy, partial small intestinal resection and extraintestinal decompression were performed. Postoperative pathology confirmed intestinal duplication and ectopic pancreas. After surgery, the patient recovered well with no complications. No recurrence was observed after more than 5 mo of follow-up. CONCLUSION: We report a new case of a young male with intussusception caused by intestinal duplication and ectopic pancreas. Surgery is the main treatment for these conditions. This study aimed to raise awareness and provide information to improve the clinical management of this rare yet serious condition.

Identifying a Hypoxia-Related Long Non-Coding RNAs Signature to Improve the Prediction of Prognosis and Immunotherapy Response in Hepatocellular Carcinoma.

Background: Both hypoxia and long non-coding RNAs (lncRNAs) contribute to the tumor progression in hepatocellular carcinoma (HCC). We sought to establish a hypoxia-related lncRNA signature and explore its correlation with immunotherapy response in HCC. Materials and Methods: Hypoxia-related differentially expressed lncRNAs (HRDELs) were identified by conducting the differential gene expression analyses in GSE155505 and The Cancer Genome Atlas (TCGA)- liver hepatocellular carcinoma (LIHC) datasets. The HRDELs landscape in patients with HCC in TCGA-LIHC was dissected by an unsupervised clustering method. Patients in the TCGA-LIHC cohort were stochastically split into the training and testing dataset. The prognostic signature was developed using LASSO (least absolute shrinkage and selection operator) penalty Cox and multivariable Cox analyses. The tumor immune microenvironment was delineated by the single-sample gene set enrichment analysis (ssGSEA) algorithm. The Tumor Immune Dysfunction and Exclusion (TIDE) algorithm was applied to evaluate the predictive value of the constructed signature in immunotherapeutic responsiveness. Results: A total of 55 HRDELs were identified through integrated bioinformatical analyses in GSE155505 and TCGA-LIHC. Patients in the TCGA-LIHC cohort were categorized into three HRDELs-specific clusters associated with different clinical outcomes. The prognostic signature involving five hypoxia-related lncRNAs ( LINC00869, CAHM, RHPN1-AS1, MKLN1-AS, and DUXAP8) was constructed in the training dataset and then validated in the testing dataset and entire TCGA-LIHC cohort. The 5-years AUC of the constructed signature for prognostic prediction reaches 0.705 and is superior to that of age, AJCC stage, and histopathological grade. Patients with high-risk scores consistently had poorer overall survival outcomes than those with low-risk scores irrespective of other clinical parameters status. The low-risk group had more abundance in activated CD8+ T cell and activated B cell and were predicted to be more responsive to immunotherapy and targeted therapy than the high-risk group. Conclusion: We established a reliable hypoxia-related lncRNAs signature that could accurately predict the clinical outcomes of HCC patients and correlate with immunotherapy response and targeted drug sensitivity, providing new insights for immunotherapy and targeted therapy in HCC.

Perianal superficial CD34-positive fibroblastic tumor: A case report.

BACKGROUND: Superficial CD34-positive fibroblast tumors (SCPFTs) are newly recognized fibroblast and myofibroblast tumors representing intermediate tumors. To the best of our knowledge, fewer than 50 cases have been reported. Perianal SCPFT has not been previously reported. CASE SUMMARY: A 55-year-old man was hospitalized upon discovering a painless perianal lump 10 d prior. Physical examination showed a lump of approximately 3 cm × 4 cm in the 7 to 8 o'clock direction in the perianal area. Perianal abscess was considered the primary diagnosis. Lump removal surgery was performed under epidural anesthesia. Postoperative pathology showed a well-circumscribed, soft tissue-derived, spindle-cell tumor with strong CD34 positivity by immunohistochemistry. The final diagnosis was perianal SCPFT. There were no complications, and the patient was followed for more than 8 mo without recurrence or metastasis. CONCLUSION: We report a case of perianal superficial CD34-positive fibroblast tumor. This rare mesenchymal neoplasm has distinctive histomorphology, which is important for diagnosis. Comprehensive consideration of clinical information, imaging, histology, and immunohistochemistry is important for diagnosis.

Effects of Nonelastic Taping and Dual Task on Kinematics and Kinetics of the Ankle Joint.

OBJECTIVES: The purpose of this experimental study was to investigate the effects of nonelastic taping and dual task on ankle kinematics and kinetics in gait analysis of healthy adults. METHODS: A total of 21 healthy adults completed trials of gait analysis using a Vicon system combining ground walking with different cognitive task conditions (none, modified Stroop color/character naming, and serial-7 subtraction), with or without nonelastic taping. Ankle kinematics and kinetics including speed, ankle plantarflexion and inversion angle, ground reaction force (GRF), and stride time variability (STV) under all conditions of taping (YES or NO) and cognitive task (none, naming, and subtraction) were characterized and analyzed with repeated-measures ANOVA. RESULTS: As regards cognitive performance, the serial-7 subtraction performance under walking conditions with and without taping was significantly poorer than simple sitting condition (P < 0.001). For kinematics and kinetics, STV showed statistically significant decrease (P=0.02) when subjects underwent taping application. Vertical GRF was significantly greater under taping than barefoot (P=0.001). Ankle plantarflexion at initial contact (IC) under the dual-task walking was significantly more than under simple walking (P=0.008). CONCLUSIONS: Applications of nonelastic taping and dual task may lead to the STV, vertical GRF, ankle plantarflexion, and speed alterations because of restricted joint range of motion and changed sensorimotor neural circuit. When healthy adults performed dual-task walking, central neural resources allocation was disturbed, leading to weakened performance in both motor and cognitive tasks.

Detection of human papillomavirus distinguishes second primary tumors from lung metastases in patients with squamous cell carcinoma of the cervix.

BACKGROUND: In patients with squamous cell carcinoma of the cervix (SCCC), a squamous cell carcinoma (SqCC) in the lung represents either a second primary tumor or metastasis. This distinction between second primary tumors and lung metastases in patients with SCCC significantly influences patient prognosis and therapy. Here, we aimed to differentiate second primary tumors from lung metastases in patients with SCCC by exploring the HPV status in SqCCs involving the lung within a large cohort. METHODS: P16 expression was assessed using immunohistochemistry on tissue microarrays including a total of 415 primary lung SqCCs and 21 lung SqCCs with prior SCCC. Following this, we performed HPV DNA typing and the sensitive RNAscope in situ method to screen all the cases for HPV E6/E7 expression, which is a more reliable indicator of transcriptively active HPV in tumor cells. RESULTS: The p16 positive expression rate was 13.7% (57/415) in primary lung SqCCs, but HPV DNA was not detected in any of the 57 primary lung SqCC cases that positively expressed p16. In contrast, HPV DNA was detected in all cases (21/21) with prior SCCC. Consistently, all 21 lung SqCCs with prior SCCC (21/21) showed extensive HPV16 E6/E7 expression. In striking contrast, none of the primary lung SqCCs (0/415) had a detectable RNAscope signal. CONCLUSIONS: HPV does not seem to play a role in the development of primary lung SqCCs. HPV detection may be helpful in distinguishing second primary tumors from lung metastases in patients with SCCC.

Dihydromyricetin induced lncRNA MALAT1-TFEB-dependent autophagic cell death in cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer. Dihydromyricetin (DHM), a Rattan tea extract, has been shown to have antitumor activity with no obvious toxicity to normal cells in vitro and in vivo. However, its efficacy in the treatment of CSCC and the underlying antitumor mechanism has not been fully elucidated yet. In our study, DHM increased autophagic flux in the A431 cells, as evidenced by the upregulation of LC3-II and downregulation of P62/SQSTM1. Moreover, the pharmacological or genetic blocking autophagy decreased DHM-induced cell death, indicating DHM triggered autophagic cell death in A431 cells. Specifically, DHM induced TFEB(Ser142) de-phosphorylation, activated TFEB nuclear translocation and increased of TFEB reporter activity, which contributed to the expression of autophagy-related genes and subsequent initiated autophagic cell death in A431 cells. Importantly, DHM decreased lncRNA MALAT1 expression and MALAT1 overexpression abrogated the effects of DHM on TFEB-dependent autophagy both in vitro and in vivo. Taken together, DHM induces CSCC cell death via inducing excessive autophagy, which is mediated through the MALAT1-TFEB pathway. Therefore, DHM may be beneficial for the development of chemotherapy for CSCC.

ß-Asarone suppresses Wnt/ß-catenin signaling to reduce viability, inhibit migration/invasion/adhesion and induce mitochondria-related apoptosis in lung cancer cells.

Lung cancer is the leading cause of cancer death worldwide. Chemotherapy is one of the most effective strategies for lung cancer treatment. However, the side effects of chemotherapy limit the application of chemotherapeutic agents. The ß-Asarone, a low-toxicity natural compound from a traditional Chinese medicinal herb, has been demonstrated to display anticancer activities in multiple cancer types. However, the anticancer activities of ß-Asarone in lung cancer have not been shown, and the underlying molecular mechanisms are still unclear. In the current study, we show that ß-Asarone displays a dose-dependent inhibitory effect on the viability of lung cancer cells. Additionally, ß-Asarone significantly suppresses the cell migration, invasion, and adhesion of lung cancer cells. Moreover, ß-Asarone induces apoptosis associated with the activation of caspase-9 and caspase-3, the upregulation of XAF1, Puma, Bax (Ser184) and Bad (Ser112), the downregulation of XIAP, Bcl-2 and Survivin, the translocation of Bax, Bad, phospho-Bax (Ser184), phospho-Bad (Ser112) and cytochrome C and the reduction of the mitochondrial membrane potential. Mechanistically, our study shows that ß-Asarone inhibits Wnt/ß-catenin signaling. Rescuing the activation of Wnt/ß-catenin signaling overcomes ß-Asarone-induced anticancer effects. Taken together, our data provide the first evidence of the anticancer effects of ß-Asarone in lung cancer, demonstrates that the inhibition of Wnt/ß-catenin signaling could be critical for ß-Asarone-induced anticancer effects. Our study thus suggests a potential application of ß-Asarone as an anticancer agent in the clinical treatment of lung cancer.

Inhibiting ROS-TFE3-dependent autophagy enhances the therapeutic response to metformin in breast cancer.

Autophagy modulation is a potential therapeutic strategy for breast cancer, and a previous study indicated that metformin exhibits significant anti-carcinogenic activity. However, the ability of metformin to induce autophagy and its role in breast cancer cell death remains unclear. In this study, we exposed MCF-7 cells to different concentrations of metformin (2.5, 5, and 10 mM) for 48 h, and metformin-induced significant apoptosis in the MCF-7 cells. The expression levels of CL-PARP (poly(ADP-ribose) polymerase 1) and the ratio of BAX to BCL-2 were significantly increased. In addition to apoptosis, we showed that metformin increased autophagic flux in MCF-7 cells, as evidenced by the upregulation of LC3-II and downregulation of P62/SQSTM1. Moreover, pharmacological or genetic blocking of autophagy increased metformin-induced apoptosis, indicating a cytoprotective role of autophagy in metformin-treated MCF-7 cells. Mechanistically, metformin-induced TFE3(Ser321) dephosphorylation activated TFE3 nuclear translocation and increased of TFE3 reporter activity, which contributed to lysosomal biogenesis and the expression of autophagy-related genes and, subsequently, initiated autophagy in MCF-7 cells. Importantly, we found that metformin triggered the generation of reactive oxygen species (ROS) in MCF-7 cells. Furthermore, N-acetyl-l-cysteine (NAC), a ROS scavenger, abrogated the effects of metformin on TFE3-dependent autophagy. Notably, TFE3 expression positively correlated with breast cancer development and poor prognosis in patients. Taken together, these data demonstrate that blocking ROS-TFE3-dependent autophagy to enhance the activity of metformin warrants further attention as a treatment strategy for breast cancer.