Role of adhesion molecules in cancer and targeted therapy.

Adhesion molecules mediate cell-to-cell and cell-to-extracellular matrix interactions and transmit mechanical and chemical signals among them. Various mechanisms deregulate adhesion molecules in cancer, enabling tumor cells to proliferate without restraint, invade through tissue boundaries, escape from immune surveillance, and survive in the tumor microenvironment. Recent studies have revealed that adhesion molecules also drive angiogenesis, reshape metabolism, and are involved in stem cell self-renewal. In this review, we summarize the functions and mechanisms of adhesion molecules in cancer and the tumor microenvironment, as well as the therapeutic strategies targeting adhesion molecules. These studies have implications for furthering our understanding of adhesion molecules in cancer and providing a paradigm for exploring novel therapeutic approaches.

Silencing AHNAK promotes nasopharyngeal carcinoma progression by upregulating the ANXA2 protein.

PURPOSE: Nasopharyngeal carcinoma (NPC) is an aggressive head and neck disease with a high incidence of distant metastases. Enlargeosomes are cytoplasmic organelles marked by, desmoyokin/AHNAK. This study aimed to evaluate the expression of AHNAK in NPC and its effect on enlargeosomes and to investigate the correlation between AHNAK expression levels and clinical NPC patient characteristics. METHODS: Primary nasopharyngeal carcinoma (NPC) and NPC specimens were evaluated by analyzing public data, and immunohistochemistry. Systematic in vitro and in vivo experiments were performed using different NPC-derived cell lines and mouse models. RESULTS: In this study, we detected AHNAK and Annexin A2(ANXA2), a protein coating the surface of enlargeosomes, in NPC samples. We found that AHNAK was down-regulated. Down-regulation of AHNAK was associated with poor overall survival in NPC patients. Moreover, transcription factor FOSL1-mediated transcriptional repression was responsible for the low expression of AHNAK by recruiting EZH2. Whereas Annexin A2 was upregulated in human NPC tissues. Upregulation of Annexin A2 was associated with lymph node metastasis and distant metastasis in NPC patients. Functional studies confirmed that silencing of AHNAK enhanced the growth, invasion, and metastatic properties of NPC cells both in vitro and in vivo. In terms of mechanism, loss of AHNAK led to an increase of annexin A2 protein level in NPC cells. Silencing ANXA2 restored NPC cells' migrative and invasive ability upon loss of AHNAK. CONCLUSION: Here, we report AHNAK as a tumor suppressor in NPC, which may act through annexin A2 oncogenic signaling in enlargeosome, with potential implications for novel approaches to NPC treatment.

Distal end of a ureteral double-J stent displaced into the contralateral ureter after percutaneous nephrolithotripsy: a case report.

We report displacement of the distal end of a ureteral double-J stent into the contralateral ureter after percutaneous nephrolithotripsy (PCNL) in a 71-year-old man with a history of left kidney stones. Postoperative computed tomography imaging showed that the distal end of the left ureteral double-J stent was displaced into the right ureter, which resulted in persistent right renal colic when the nephrostomy tube was clipped and continuous urine leakage from the nephrostomy opening after the nephrostomy tube was removed. After the cystoscopic adjustment of the ureteral stent, the patient recovered uneventfully and was discharged home the next day.

MCM4 acts as a biomarker for LUAD prognosis.

MCM4 forms the pre-replication complex (MCM2-7) with five other minichromosome maintenance (MCM) proteins. This complex binds to replication origins at G1 stage in cell cycle process, playing a critical role in DNA replication initiation. Recently, MCM4 is reported to have a complex interaction with multiple cancer progression, including gastric, ovarian and cervical cancer. Here, this study mainly focused on the expression of MCM4 and its values in lung adenocarcinoma (LUAD). MCM4 was highly expressed in LUAD tumours and cells, and had an important effect on the overall survival. Overexpression of MCM4 promoted the proliferation, and suppressed the apoptosis in LUAD cells. However, MCM4 silence led to the opposite results. In vivo, knockdown of MCM4 inhibited tumour volume and weight in xenograft mouse model. As a member of DNA helicase, knockdown of MCM4 caused cell cycle arrest at G1 stage through inducing the expression of P21, a CDK inhibitor. These findings indicate that MCM4 may be a possible new therapeutic target for LUAD in the future.

Yin Yang 1 suppresses tumor invasion and metastasis in nasopharyngeal carcinoma by negatively regulating eIF4E transcriptional activity and expression.

Tumor metastasis is a leading cause of death in nasopharyngeal carcinoma (NPC) patients. Previous research has identified that transcription factor Yin Yang 1 (YY1) acts as a tumor suppressor that inhibits cell proliferation and tumor growth in NPC; however, the role and the molecular mechanisms of YY1 in NPC invasion and metastasis remain unclear. In this study, we discovered that YY1 could inhibit the migration and invasion of NPC cells in vitro as well as NPC xenograft tumor metastasis in vivo. Furthermore, we identified eIF4E as a direct downstream target of YY1, and YY1 could negatively regulate the expression of eIF4E at transcriptional level. Moreover, we found that eIF4E promoted the migration and invasion of NPC cells as well as NPC lung metastasis, suggesting its potential as a pro-metastatic mediator in NPC. Importantly, restoring eIF4E expression could partially reverse the inhibitory effects of YY1 on NPC malignancy. In consistent with these findings, the expression of YY1 was downregulated while eIF4E was upregulated in NPC patients with metastasis, and there was a negative correlation between YY1 and eIF4E expression. Collectively, our results indicate that YY1 suppresses the invasion and metastasis of NPC by negatively regulating eIF4E transcription. Therefore, targeting the YY1/eIF4E transcriptional axis could be a potential therapeutic strategy for the treatment of patients with NPC.

NOP2/Sun RNA methyltransferase 2 is a potential pan-cancer prognostic biomarker and is related to immunity.

BACKGROUND: NOP2/Sun RNA methyltransferase 2 (NSUN2), an important methyltransferase of m5C, has been poorly studied in cancers, and the relationship between NSUN2 and immunity remains largely unclear. Therefore, the purpose of this study was to explore the expression and prognostic value of NSUN2 and the role of NSUN2 in immunity in cancers. METHODS: The TIMER, CPTAC and other databases were used to analyze the expression of NSUN2, its correlation with clinical stage and its prognostic value across cancers. Moreover, the TISIDB, TIMER2.0 and Sangerbox platform were used to depict the relationships between NSUN2 and immune molecular subtypes, tumor-infiltrating lymphocytes (TILs), immune checkpoints (ICPs) and immunoregulatory genes. Furthermore, the NSUN2-interacting proteins and related genes as well as the coexpression networks of NSUN2 in LIHC, LUAD and HNSC were explored with the STRING, DAVID, GEPIA2 and LinkedOmics databases. Finally, the subcellular location and function of NSUN2 in HepG2, A549 and 5-8F cells were investigated by performing immunofluorescence, CCK-8 and wound healing assays. RESULTS: Overall, NSUN2 was highly expressed and related to a poor prognosis in most types of cancers and was also significantly associated with immune molecular subtypes in some cancer types. Furthermore, NSUN2 was significantly associated with the levels of ICPs and immunoregulatory genes. In addition, NSUN2 was found to be involved in a series of immune-related biological processes, such as the humoral immune response in LIHC and LUAD and T-cell activation and B-cell activation in HNSC. Immunofluorescence and CCK-8 assays also confirmed that NSUN2 was widely expressed in the nucleus and cytoplasm, and overexpression of NSUN2 promoted the proliferation and migration of HepG2, A549 and 5-8F cells. NSUN2 was also confirmed to positively regulate the expression of PD-L1. CONCLUSION: NSUN2 serves as a pan-cancer prognostic biomarker and is correlated with the immune infiltration of tumors.

YWHAH activates the HMGA1/PI3K/AKT/mTOR signaling pathway by positively regulating Fra-1 to affect the proliferation of gastric cancer cells.

Fos-related antigen 1 (Fra-1) is a nuclear transcription factor that regulates cell growth, differentiation, and apoptosis. It is involved in the proliferation, invasion, apoptosis and epithelial mesenchymal transformation of malignant tumor cells. Fra-1 is highly expressed in gastric cancer (GC), affects the cycle distribution and apoptosis of GC cells, and participates in GC occurrence and development. However, the detailed mechanism of Fra-1 in GC is unclear, such as the identification of Fra-1-interacting proteins and their role in GC pathogenesis. In this study, we identified tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein eta (YWHAH) as a Fra-1-interacting protein in GC cells using co-immunoprecipitation combined with liquid chromatography-tandem mass spectrometry. Experiments showed that YWHAH positively regulated Fra-1 mRNA and protein expression, and affected GC cell proliferation. Whole proteome analysis showed that Fra-1 affected the activity of the high mobility group AT-hook 1 (HMGA1)/phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway in GC cells. Western blotting and flow cytometry confirmed that YWHAH activated HMGA1/PI3K/AKT/mTOR signaling pathway by positively regulating Fra-1 to affect GC cell proliferation. These results will help to discover new molecular targets for the early diagnosis, treatment, and prognosis prediction of GC.

Super Enhancer Driven Hyaluronan Synthase 3 Promotes Malignant Progression of Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is a malignant tumor of the head and neck with high metastatic and invasive nature. Super enhancers (SEs) control the expression of cell identity genes and oncogenes during tumorigenesis. As a glycosaminoglycan in the tumor microenvironment, hyaluronan (HA) is associated with cancer development. High expression of hyaluronan synthase 3 (HAS3) resulted in HA deposition, which promoted the growth of cancer cell. However, its role in NPC development remains elusive. We demonstrated that the levels of HAS3 mRNA or protein were increased in NPC cell lines. Transcription of HAS3 is associated with SE. Disruption of SE by bromodomain containing 4 (BRD4) inhibitor JQ1 resulted in downregulation of HAS3 and inhibition of cell proliferation and invasiveness in NPC cells. Inhibition of HA synthesis by HAS inhibitor 4-MU suppressed cell growth and invasion of NPC cells, whereas HA treatment exerted opposite effects. Genetically silencing HAS3 in HK1 and FaDu NPC cells attenuated cell proliferation and mobility, while re-expression of HAS3 enhanced malignant potential of CNE1 and CNE2 NPC cells. Furthermore, loss of HAS3 impaired metastatic potential of HK1 cells in nude mice. Mechanistically, inhibition of HA synthesis by chemical inhibitor or silencing HAS3 led to reduction of the levels of phosphorylation of EGFR, AKT, and ERK proteins. In contrast, exogenous HA treatment or forced expression of HAS3 activated EGFR/AKT/ERK signaling cascade. This study suggested that HAS3 is driven by SE and overexpressed in NPC. High expression of HAS3 promotes the malignant features of NPC via activation of EGFR/AKT/ERK signaling pathway.

Iron-Rich Semiconducting Polymer Dots for the Combination of Ferroptosis-Starvation and Phototherapeutic Cancer Therapy.

Chemodynamic therapy (CDT) has emerged as an outstanding antitumor therapeutic method due to its selectivity and utilization of tumor microenvironment. However, there are still unmet requirements to achieve a high antitumor efficiency, including the tumor accumulation of catalyst and enrichment of reactants of Fenton reaction. Here, an iron-loaded semiconducting polymer dot modified with glucose oxidase (Pdot@Fe@GOx) is reported to deliver iron ions into tumor tissues and in situ generation of hydrogen peroxide in tumors. On one hand, Pdot@Fe@GOx converts glucose to gluconic acid and hydrogen peroxide (H2 O2 ) in tumor, which not only consumes glucose of tumor cells, but also provides the H2 O2 for the following Fenton reaction. On the other hand, the Pdot@Fe@GOx delivers active iron ions in tumor to perform CDT with the combination of the generated H2 O2 . In addition, the Pdot@Fe@GOx has both photothermal and photodynamic effects under the irradiation of near-infrared laser, which can improve and compensate the CDT effect to kill cancer cells. This Pdot@Fe@GOx-based multiple-mode therapeutic strategy has successfully achieved a synergistic anticancer effect with minimal side effects and has the potential to be translated into preclinical setting for tumor therapy.

Circular RNA circRILPL1 promotes nasopharyngeal carcinoma malignant progression by activating the Hippo-YAP signaling pathway.

Circular RNAs (circRNAs) play an important regulatory role in the pathogenesis and progression of nasopharyngeal carcinoma (NPC), which have not been thoroughly elucidated. In this study, we revealed for the first time that circRILPL1 was upregulated in NPC, weakened adhesion and decreased stiffness of NPC cells, and promoted NPC proliferation and metastasis in vitro and in vivo. Mechanistically, circRILPL1 inhibited the LATS1-YAP kinase cascade by binding to and activating ROCK1, resulting in decrease of YAP phosphorylation. Binding and cooperating with transport receptor IPO7, circRILPL1 promoted the translocation of YAP from the cytoplasm to the nucleus, where YAP enhanced the transcription of cytoskeleton remodeling genes CAPN2 and PXN. By which, circRILPL1 contributed to the pathogenesis of NPC. Our results demonstrated that circRILPL1 promoted the proliferation and metastasis of NPC through activating the Hippo-YAP signaling pathway by binding to both ROCK1 and IPO7. Highly expressed circRILPL1 in NPC may serve as an important biomarker for tumor diagnosis and may also be a potential therapeutic target.

Overview and countermeasures of cancer burden in China.

Cancer is one of the leading causes of human death worldwide. Treatment of cancer exhausts significant medical resources, and the morbidity and mortality caused by cancer is a huge social burden. Cancer has therefore become a serious economic and social problem shared globally. As an increasingly prevalent disease in China, cancer is a huge challenge for the country's healthcare system. Based on recent data published in the Journal of the National Cancer Center on cancer incidence and mortality in China in 2016, we analyzed the current trends in cancer incidence and changes in cancer mortality and survival rate in China. And also, we examined several key risk factors for cancer pathogenesis and discussed potential countermeasures for cancer prevention and treatment in China.

Understanding the roles and regulation patterns of circRNA on its host gene in tumorigenesis and tumor progression.

Circular RNAs (circRNAs) are a novel type of endogenous non-coding RNAs, which are covalently closed loop structures formed by precursor mRNAs (pre-mRNAs) through back-splicing. CircRNAs are abnormally expressed in many tumors, and play critical roles in a variety of tumors as oncogenes or tumor suppressor genes by sponging miRNAs, regulating alternative splicing and transcription, cis-regulating host genes, interacting with RNA binding proteins (RBPs) or encoding polypeptides. Among them, the regulation of circRNAs on their corresponding host genes is a critical way for circRNAs to exit their functions. Accumulating evidence suggests that circRNAs are able to regulate the expression of host genes at the transcriptional level, post-transcriptional level, translational level, post-translational level, or by encoding polypeptides. Therefore, this paper mainly summarized the roles and association of circRNAs and their corresponding host genes in tumorigenesis and tumor progression, generalized the circRNAs that function synergistically or antagonistically with their host genes, and elaborated the mechanisms of mutual regulation between circRNAs and their host genes. More importantly, this review provides specific references for revealing the potential application of circRNAs combined with their host genes in tumor diagnosis, treatment and prognosis.

Dissecting the roles and clinical potential of YY1 in the tumor microenvironment.

Yin-Yang 1 (YY1) is a member of the GLI-Kruppel family of zinc finger proteins and plays a vital dual biological role in cancer as an oncogene or a tumor suppressor during tumorigenesis and tumor progression. The tumor microenvironment (TME) is identified as the "soil" of tumor that has a critical role in both tumor growth and metastasis. Many studies have found that YY1 is closely related to the remodeling and regulation of the TME. Herein, we reviewed the expression pattern of YY1 in tumors and summarized the function and mechanism of YY1 in regulating tumor angiogenesis, immune and metabolism. In addition, we discussed the potential value of YY1 in tumor diagnosis and treatment and provided a novel molecular strategy for the clinical diagnosis and treatment of tumors.

RNA modifications in cancer.

Currently, more than 170 modifications have been identified on RNA. Among these RNA modifications, various methylations account for two-thirds of total cases and exist on almost all RNAs. Roles of RNA modifications in cancer are garnering increasing interest. The research on m6A RNA methylation in cancer is in full swing at present. However, there are still many other popular RNA modifications involved in the regulation of gene expression post-transcriptionally besides m6A RNA methylation. In this review, we focus on several important RNA modifications including m1A, m5C, m7G, 2'-O-Me, Ψ and A-to-I editing in cancer, which will provide a new perspective on tumourigenesis by peeking into the complex regulatory network of epigenetic RNA modifications, transcript processing, and protein translation.

Biocompatibility and Biological Effects of Surface-Modified Conjugated Polymer Nanoparticles.

Semiconductiong polymer nanoparticles (Pdots) have a wide range of applications in biomedical fields including biomolecular probes, tumor imaging, and therapy. However, there are few systematic studies on the biological effects and biocompatibility of Pdots in vitro and in vivo. The physicochemical properties of Pdots, such as surface modification, are very important in biomedical applications. Focusing on the central issue of the biological effects of Pdots, we systematically investigated the biological effects and biocompatibility of Pdots with different surface modifications and revealed the interactions between Pdots and organisms at the cellular and animal levels. The surfaces of Pdots were modified with different functional groups, including thiol, carboxyl, and amino groups, named Pdots@SH, Pdots@COOH, and Pdots@NH2, respectively. Extracellular studies showed that the modification of sulfhydryl, carboxyl, and amino groups had no significant effect on the physicochemical properties of Pdots, except that the amino modification affected the stability of Pdots to a certain extent. At the cellular level, Pdots@NH2 reduced cellular uptake capacity and increased cytotoxicity due to their instability in solution. At the in vivo level, the body circulation and metabolic clearance of Pdots@SH and Pdots@COOH were superior to those of Pdots@NH2. The four kinds of Pdots had no obvious effect on the blood indexes of mice and histopathological lesions in the main tissues and organs. This study provides important data for the biological effects and safety assessment of Pdots with different surface modifications, which pave the way for their potential biomedical applications.

Secular trends of suicide risk for residents in mainland China (2004 to 2019): An updated age-period-cohort analysis.

BACKGROUND: The overall suicide rate in China has dropped substantially since the 1990s, but a slowdown in the decrease and even a reversing trend was observed in specific groups in recent years. This study aims to investigate the latest suicide risk in mainland China by using the age-period-cohort (APC) analysis. METHOD: This population-based multiyear cross-sectional study included Chinese ages 10 to 84 years using data from the China Health Statistical Yearbook (2005-2020). Data were analyzed by the APC analysis and intrinsic estimator (IE) technique. RESULTS: The data satisfactorily fit the constructed APC models. The cohort effect indicated a high risk of suicide among people birth in 1920-1944 and a sharp decline in the 1945-1979 cohort. The lowest risk occurred in the 1980-1994 cohort before a sharp increase in generation Z (birth years in 1995-2009). The period effect showed a declining trend since 2004. The age effect indicated that the suicide risk increased over time, except for a gradual decline from age 35 to 49. The suicide risk increased greatly in adolescents and reached the highest among the elderly. LIMITATIONS: The aggregated population-level data and the non-identifiability of the APC model could result in bias in the accuracy of results in this study. CONCLUSIONS: This study successfully updated the Chinese suicide risk from the age, period and cohort perspective using the latest available data (2004-2019). The findings enhance the understanding of suicide epidemiology and provide evidence supporting policies and strategies at the macro-level for suicide prevention and management. Immediate action is needed to focus on a national suicide prevention strategy that targets generation Z, adolescents and the elderly which will require a collaborative effort by government officials, public/community health planners and health care agencies.

BRD7 inhibits enhancer activity and expression of BIRC2 to suppress tumor growth and metastasis in nasopharyngeal carcinoma.

BRD7 functions as a crucial tumor suppressor in numerous malignancies including nasopharyngeal carcinoma (NPC). However, its function and exact mechanisms involved in tumor progression are not well understood. Here, we found that the B7BS was a potential enhancer region of BIRC2, and BRD7 negatively regulated the transcriptional activity and expression of BIRC2 by targeting the activation of the BIRC2 enhancer. Moreover, BIRC2 promoted cell proliferation, migration, invasion as well as xenograft tumor growth and metastasis in vivo, thus functioning as an oncogene in NPC. Furthermore, the recovery of BIRC2 expression could rescue the inhibitory effect of BRD7 on cell proliferation, migration, invasion and xenograft tumor growth and metastasis. In addition, BIRC2 was highly-expressed in NPC tissues, and positively correlated with the TNM stage and negatively correlated with the expression of BRD7. Therefore, these results suggest that BRD7 suppresses tumor growth and metastasis thus functioning as a tumor suppressor at least partially by negatively regulating the enhancer activity and expression of BIRC2, and targeting the BRD7/BIRC2 regulation axis might be a potential strategy for the diagnosis and treatment of NPC.

Effects of combining acupuncture with exercise training on relieving dyspnea and improving exercise tolerance in chronic obstructive pulmonary disease patients: a protocol for a single-blind, randomized, sham-controlled trial.

BACKGROUND: Exercise training is beneficial for patients with chronic obstructive pulmonary disease (COPD). However, the effect of exercise training is limited by patients' impaired exercise capacity, exertional dyspnea and other respiratory problems. Acupuncture, as a reliable and safe therapy, is effective in reducing dyspnea, relieving respiratory muscle fatigue, and improving exercise capacity of COPD patients. However, it is not known whether the combination of exercise training and acupuncture reduces dyspnea and improves quality of life of COPD patients or induces more pronounced effects in dyspnea and exercise tolerance. This trial aims to determine whether acupuncture enhances the effect of exercise training in COPD patients compared to sham acupuncture. METHODS: In this single-blind, randomized, sham-controlled trial, 70 COPD patients will be enrolled and randomly assigned (1:1) to the following 2 groups: (I) real acupuncture and exercise training group; and (II) sham acupuncture and exercise training group. For acupoint selection, CV 4, CV 12, CV 17, ST 40, ST 16 and ST 25 will be used for all patients. For sham acupuncture group, Streitberger placebo needles will be used. A single-blind method will be adopted in this trial. Data collectors and statisticians will be blinded in this trial, only the acupuncturists will know the group allocation. The intervention will be conducted 3 times a week for 8 weeks, totaling 24 treatments. Patients will be evaluated at the baseline, after 14 treatments during the 5th week, after 24 treatments during the 8th week, and at a 5-month follow-up period. The primary outcomes will be assessed by a modified British medical research council questionnaire (mMRC), COPD assessment test (CAT), and 6-minute walk test (6MWT). The secondary outcomes will be measured by changes in variables from the lung function test, cardiopulmonary exercise testing, and blood gas analysis. Two-independent sample t-tests will be used to compare differences in the changes in all outcome measures after the intervention between two groups. Safety evaluation will be performed at each treatment visit and assessment by recording adverse events (AE) in the AE Report Form. DISCUSSION: This study will help to determine whether acupuncture increases the benefits obtained from exercise training in COPD patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR1900028627. Registered on December 29, 2019.

The Emerging Roles and Clinical Potential of circSMARCA5 in Cancer.

Circular RNAs (circRNAs) are a type of endogenous non-coding RNA and a critical epigenetic regulation way that have a closed-loop structure and are highly stable, conserved, and tissue-specific, and they play an important role in the development of many diseases, including tumors, neurological diseases, and cardiovascular diseases. CircSMARCA5 is a circRNA formed by its parental gene SMARCA5 via back splicing which is dysregulated in expression in a variety of tumors and is involved in tumor development with dual functions as an oncogene or tumor suppressor. It not only serves as a competing endogenous RNA (ceRNA) by binding to various miRNAs, but it also interacts with RNA binding protein (RBP), regulating downstream gene expression; it also aids in DNA damage repair by regulating the transcription and expression of its parental gene. This review systematically summarized the expression and characteristics, dual biological functions, and molecular regulatory mechanisms of circSMARCA5 involved in carcinogenesis and tumor progression as well as the potential applications in early diagnosis and gene targeting therapy in tumors.