The role and molecular mechanism of NOP16 in the pathogenesis of nasopharyngeal carcinoma.

We aimed to explore the effects of NOP16 on the pathogenesis of nasopharyngeal carcinoma (NPC) and the related mechanism. In this study, the expression level of NOP16 in NPC tissues and adjacent tissues was measured by qRT-polymerase chain reaction (PCR) and immunohistochemistry (IHC) tests. In the in vitro study, the expression levels of NOP16 and RhoA/phosphatidylinositol 3-kinase (PI3K)/Akt/c-Myc and IKK/IKB/NF-κB signalling pathway-related proteins in NPC cells were measured by qRT-PCR and Western blot (WB). CCK8 assays and colony formation assays were used to detect cell proliferation. Transwell assays were used to detect the migration and invasion ability of NPC cells. Flow cytometry and WB were used to measure the level of apoptosis. For the in vivo study, NPC xenograft models were established in nude mice, and tumour weight and volume were recorded. The expression levels of NOP16 and RhoA/PI3K/Akt/c-Myc signalling pathway-related proteins and mRNAs were measured by immunofluorescence, qRT-PCR and WB experiments. In clinical samples, the results of qRT-PCR and IHC experiments showed that the expression level of NOP16 was significantly increased in NPC tissues. In the in vitro study, the results of qRT-PCR and WB experiments showed that NOP16 was significantly increased in NPC cells. The CCK8 assay, colony formation assay, transwell assay and flow cytometry results showed that knocking out NOP16 inhibited the proliferation, migration and invasion of NPC cells and increased apoptosis. WB results showed that knocking out NOP16 inhibited the RhoA/PI3K/Akt/c-Myc and IKK/IKB/NF-κB signalling pathways. These effects were reversed by 740Y-P (PI3K activator). In the in vivo study, knockdown of NOP16 reduced tumour volume and weight and inhibited the RhoA/PI3K/Akt/c-Myc signalling pathway. In conclusion, knockdown of NOP16 inhibited the proliferation, migration and invasion of NPC cells and induced apoptosis by inhibiting the RhoA/PI3K/Akt/c-Myc and IKK/IKB/NF-κB pathways, leading to the malignant phenotype of NPC.

Institutionally validated nomogram predicting prognosis for older patients with nonmetastatic nasopharyngeal carcinoma.

Aim: Older adult patients with nonmetastatic nasopharyngeal carcinoma (NPC) have poor outcomes relative to younger patients. The authors' group established a nomogram to predict the overall survival of older adults with NPC and inform patient management. Methods: Cases with NPC (n = 782) were enrolled in this study; clinical data in the Surveillance, Epidemiology, and End Results database from 2010 to 2015 served as the training cohort (n = 657), and patients from Jiangxi Cancer Hospital (n = 125) served as the external validation cohort. Results: Training and external validation cohort C-index, receiver operator characteristics curves and calibration curves showed that our nomogram has great predictive ability. Conclusions: Compared with tumor-node-metastasis staging, this nomogram can help clinicians better predict the prognosis of older adults with nonmetastatic NPC.

It is well known that more than 80% of newly diagnosed NPC patients are nonmetastatic. Older adult patients with nonmetastatic nasopharyngeal carcinoma have a poor chance of survival relative to younger patients. With the world's aging population, the treatment of older adults with nonmetastatic NPC has attracted more attention from clinicians. The use of the American Joint Committee on Cancer staging system alone has significant shortcomings in predicting survival outcomes. Therefore, the authors developed a predictive tool by combining more prognostic factors with a specific multivariable statistical model, including age, tumor stage, node stage and treatment type, which is helpful for clinicians to more accurately evaluate the prognosis of patients.

Limited recurrence distance of glioblastoma under modern radiotherapy era.

BACKGROUND: The optimal treatment volume for Glioblastoma multiforme (GBM) is still a subject of debate worldwide. The current study was aimed to determine the distances between recurring tumors and the edge of primary lesions, and thereby provide evidence for accurate target area delineation. METHODS: Between October 2007 and March 2019, 68 recurrent patients with GBM were included in our study. We measured the distance from the initial tumor to the recurrent lesion of GBM patients by expanding the initial gross tumor volume (GTV) to overlap the center of recurrent lesion, with the help of the Pinnacle Treatment Planning System. RESULTS: Recurrences were local in 47(69.1%) patients, distant in 12(17.7%) patients, and both in 9(13.2%) patients. Factors significantly influencing local recurrence were age (P = 0.049), sex (P = 0.049), and the size of peritumoral edema (P = 0.00). A total number of 91 recurrent tumors were analyzed. All local recurrences occurred within 2 cm and 94.8% (55/58) occurred within 1 cm of the original GTV based on T1 enhanced imaging. All local recurrences occurred within 1.5 cm and 98.3%(57/58) occurred within 0.5 cm of the original GTV based on T2-FLAIR imaging. 90.9% (30/33) and 81.8% (27/33) distant recurrences occurred >3 cm of T1 enhanced and T2-Flair primary tumor margins, respectively. CONCLUSIONS: The 1 cm margin from T1 enhanced lesions and 0.5 cm margin from T2-Flair abnormal lesions could cover 94.8 and 98.3% local recurrences respectively, which deserves further prospective study as a limited but effective target area.

Potential roles of mesenchymal stromal cells in islet allo- and xenotransplantation for type 1 diabetes mellitus.

Islet transplantation is poised to play an important role in the treatment of type 1 diabetes mellitus (T1DM). However, there are several challenges limiting its widespread use, including the instant blood-mediated inflammatory reaction, hypoxic/ischemic injury, and the immune response. Mesenchymal stem/stromal cells (MSCs) are known to exert regenerative, immunoregulatory, angiogenic, and metabolic properties. Here, we review recent reports on the application of MSCs in islet allo- and xenotransplantation. We also document the clinical trials that have been undertaken or are currently underway, relating to the co-transplantation of islets and MSCs. Increasing evidence indicates that co-transplantation of MSCs prolongs islet graft survival by locally secreted protective factors that reduce immune reactivity and promote vascularization, cell survival, and regeneration. MSC therapy may be a promising option for islet transplantation in patients with T1DM.

Origin recognition complex subunit 1 regulates cell growth and metastasis in glioma by altering activation of ERK and JNK signaling pathway.

Origin recognition complex subunit 1(ORC1) is reported to be closely associated with the cell cycle. However, studies on the role of ORC1 in glioma remain undefined. The aim of the present study was to determine whether ORC1 affects cell migration, invasion, apoptosis, and proliferation and to explore the possible underlying mechanism. GEO database analysis indicated that ORC1 was significantly upregulated in glioma, while Gene set enrichment analysis (GSEA) analysis indicated that ORC1 primarily regulated the cell cycle and affects apoptotic signaling pathways. Analysis of protein-protein interaction (PPI) and gene ontology (GO) to further study the relevant mechanisms revealed that the function of the interaction between proteins and ORC1 was primarily concentrated in the regulation of cell cycle, and apoptosis played a critical role in the whole PPI network. Western blot assay and RT-PCR assay indicated that ORC1 was significantly upregulated in glioma tissues. Western blot assay and RT-PCR indicated that ORC1 was significantly upregulated in glioma cell lines. Cell migration, invasion, apoptosis, and proliferation were detected using Transwell and wound healing assays, flow cytometry, colony formation, and CCK8, respectively. Furthermore, OCR1 inhibition reduced invasion and migration, promoted cell apoptosis. In addition, OCR1 overexpression promoted cell proliferation and induced G2 phase arrest. Moreover, OCR1 downregulation suppressed activation of the ERK/JNK signaling pathway. The effects of ORC1 on biological processes were reversed by ERK and JNK inhibitors. These results indicate that ORC1 could be a novel prognostic marker of glioma via the activation of the ERK/JNK signaling pathway.

ZBTB7A functioned as an oncogene in colorectal cancer.

BACKGROUND: Despite zinc finger and BTB domain-containing 7A (ZBTB7A) documented importance in multiple tumors, the function and clinical value in Colorectal cancer (CRC) remain elusive. The aim of this study was to evaluate the functional roles and the clinical value of ZBTB7A in CRC progression. METHODS: The level of ZBTB7A was detected in a large cohort of CRC patients (n = 189) by immunohistochemistry (IHC), and we analyzed the diagnostic and prognostic value of the protein. In addition, the functional roles of ZBTB7A on CRC were explored in vitro and in vivo. RESULTS: Survival analyses indicated that patients with high ZBTB7A expression made the prognosis worse (P = 0.024). Functionally, knockdown of ZBTB7A could markedly inhibit tumor proliferation in vitro and in vivo, whereas ZBTB7A overexpression displayed the opposite results. CONCLUSIONS: ZBTB7A was associated with poor survival outcomes and functioned as an oncogene in CRC patients, indicating that it is a potential prognostic biomarker and therapeutic target for CRC patients.

A review of matrix metalloproteinase-2-sensitive nanoparticles as a novel drug delivery for tumor therapy.

Matrix metalloproteinase-2 (MMP-2)-responsive nanodrug vehicles have garnered significant attention as antitumor drug delivery systems due to the extensive research on matrix metalloproteinases (MMPs) within the tumor extracellular matrix (ECM). These nanodrug vehicles exhibit stable circulation in the bloodstream and accumulate specifically in tumors through various mechanisms. Upon reaching tumor tissues, their structures are degraded in response to MMP-2 within the ECM, resulting in drug release. This controlled drug release significantly increases drug concentration within tumors, thereby enhancing its antitumor efficacy while minimizing side effects on normal organs. This review provides an overview of MMP-2 characteristics, enzyme-sensitive materials, and current research progress regarding their application as MMP-2-responsive nanodrug delivery system for anti-tumor drugs, as well as considering their future research prospects. In conclusion, MMP-2-sensitive drug delivery carriers have a broad application in all kinds of nanodrug delivery systems and are expected to become one of the main means for the clinical development and application of nanodrug delivery systems in the future.

Quantitative measurement of optical attenuation coefficients of cell lines CNE1, CNE2, and NP69 using optical coherence tomography.

The radiotherapy-related types of nasopharyngeal carcinoma (NPC) have been established, which give the most effective treatment for NPC patients using the individual therapy. To diagnose the types of NPC, we assess the general NPC cell lines CNE1, CNE2 and normal nasopharyngeal cell line NP69 using optical coherence tomography (OCT) in two steps: firstly, the OCT images of the three different types of cell pellets are captured. Secondly, by fitting Beer's law to the averaged A-scans in these OCT datasets, the attenuation coefficients (µ t ) of the cells can be extracted. The median attenuation coefficients (interquartile range) of CNE1, CNE2, and NP69 are 5.58 mm(-1) (IQR 5.55 to 5.65 mm(-1)), 5.91 mm(-1) (IQR 5.82 to 5.88 mm(-1)), and 8.96 mm(-1) (IQR 8.80 to 9.47 mm(-1)), respectively. The distinguishable quantitative OCT analysis (by µ t ) shows that the types of NPC could potentially be differentiated in real time and noninvasive.

Formulation and Evaluation on Synergetic Anti-Hepatoma Effect of a Chemically Stable and Release-Controlled Nanoself-Assembly with Natural Monomers.

Introduction: Hepatoma is the leading cause of death among liver diseases worldwide. Modern pharmacological studies suggest that some natural monomeric compounds have a significant effect on inhibiting tumor growth. However, poor stability and solubility, and side effects are the main factors limiting the clinical application of natural monomeric compounds. Methods: In this paper, drug-co-loaded nanoself-assemblies were selected as a delivery system to improve the chemical stability and solubility of Tanshinone II A and Glycyrrhetinic acid, and to produce a synergetic anti-hepatoma effect. Results: The study suggested that the drug co-loaded nanoself-assemblies showed high drug loading capacity, good physical and chemical stability, and controlled release. In vitro cell experiments verified that the drug-co-loaded nanoself-assemblies could increase the cellular uptake and cell inhibitory activity. In vivo studies verified that the drug co-loaded nanoself-assemblies could prolong the MRT0-∞, increase accumulation in tumor and liver tissues, and show strong synergistic anti-tumor effect and good bio-safety in H22 tumor-bearing mice. Conclusion: This work indicates that natural monomeric compounds co-loaded nanoself-assemblies would be a potential strategy for the treatment of hepatoma.

Camrelizumab plus famitinib in patients with recurrent or metastatic nasopharyngeal carcinoma treated with PD-1 blockade: data from a multicohort phase 2 study.

Background: Treatment options for patients with recurrent/metastatic nasopharyngeal carcinoma (RM-NPC) are not clear after progression on previous treatment with PD-(L)1 inhibitor; critical gaps in evidence remain for such cases. Immunotherapy combined with antiangiogenic therapy has been reported to have synergistic antitumor activity. Therefore, we evaluated the efficacy and safety of camrelizumab plus famitinib in patients with RM-NPC who failed treatment with PD-1 inhibitor-containing regimens. Methods: This multicenter, adaptive Simon minimax two-stage, phase II study enrolled patients with RM-NPC refractory to at least one line of systemic platinum-containing chemotherapy and anti-PD-(L)1 immunotherapy. The patient received camrelizumab 200 mg every 3 weeks and famitinib 20 mg once per day. The primary endpoint was objective response rate (ORR), and the study could be stopped early as criterion for efficacy was met (>5 responses). Key secondary endpoints included time to response (TTR), disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), overall survival (OS), and safety. This trial was registered with ClinicalTrials.gov, NCT04346381. Findings: Between October 12, 2020, and December 6, 2021, a total of 18 patients were enrolled since six responses were observed. The ORR was 33.3% (90% CI, 15.6-55.4) and the DCR was 77.8% (90% CI, 56.1-92.0). The median TTR was 2.1 months, the median DoR was 4.2 months (90% CI, 3.0-not reach), and the median PFS was 7.2 months (90% CI, 4.4-13.3), with a median follow-up duration of 16.7 months. Treatment-related adverse events (TRAEs) of grade ≥3 were reported in eight (44.4%) patients, with the most common being decreased platelet count and/or neutropenia (n = 4, 22.2%). Treatment-related serious AEs occurred in six (33.3%) patients, and no deaths occurred due to TRAEs. Four patients developed grade ≥3 nasopharyngeal necrosis; two of them developed grade 3-4 major epistaxis, and they were cured by nasal packing and vascular embolization. Interpretation: Camrelizumab plus famitinib exhibited encouraging efficacy and tolerable safety profiles in patients with RM-NPC who failed frontline immunotherapy. Further studies are needed to confirm and expand these findings. Funding: Jiangsu Hengrui Pharmaceutical Co., Ltd.

Identifying FGA peptides as nasopharyngeal carcinoma-associated biomarkers by magnetic beads.

Early diagnosis and treatment is known to improve prognosis for nasopharyngeal carcinoma (NPC). The study determined the specific peptide profiles by comparing the serum differences between NPC patients and healthy controls, and provided the basis for the diagnostic model and identification of specific biomarkers of NPC. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) can be used to detect the molecular mass of peptides. Mass spectra of peptides were generated after extracting and purification of 40 NPC samples in the training set, 21 in the single center validation set and 99 in the multicenter validation set using weak cationic-exchanger magnetic beads. The spectra were analyzed statistically using FlexAnalysis™ and ClinProt™ bioinformatics software. The four most significant peaks were selected out to train a genetic algorithm model to diagnose NPC. The diagnostic sensitivity and specificity were 100% and 100% in the training set, 90.5% and 88.9% in the single center validation set, 91.9% and 83.3% in the multicenter validation set, and the false positive rate (FPR) and false negative rate (FNR) were obviously lower in the NPC group (FPR, 16.7%; FNR, 8.1%) than in the other cancer group (FPR, 39%; FNR, 61%), respectively. So, the diagnostic model including four peptides can be suitable for NPC but not for other cancers. FGA peptide fragments identified may serve as tumor-associated biomarkers for NPC.

Increased pretreatment levels of serum LDH and ALP as poor prognostic factors for nasopharyngeal carcinoma.

Serum enzymes that play potential roles in tumor growth have recently been reported to have prognostic relevance in a diverse array of tumors. However, prognosis-related serum enzymes are rarely reported for nasopharyngeal carcinoma(NPC). To clarify whether the level of serum enzymes is linked to the prognosis of NPC, we reviewed the pretreatment data of lactate dehydrogenase(LDH), alkaline phosphatase (ALP), and glutamyl transferase (GGT) in 533 newly diagnosed NPC patients who underwent radical radiotherapy between May 2002 and October 2003 at Sun Yat-sen University Cancer Center. Patients were grouped according to the upper limit of normal values of LDH, ALP, and GGT. The Kaplan-Meier method and log-rank test were used for selecting prognostic factors from clinical characteristics and serum enzymes, and the chi-square test was applied to analyze the relationships of clinical characteristics and serum enzymes. Finally, a Cox proportional hazards model was used to identify the independent prognostic factors. We found that increased levels of LDH had poor effects on both overall survival and distant metastasis-free survival (P = 0.009 and 0.035, respectively), and increased pretreatment level of serum ALP had poor effects on both overall survival and local recurrence-free survival (P = 0.037 and 0.039, respectively). In multivariate analysis, increased LDH level was identified as an independent prognostic factor for overall survival. Therefore, we conclude that increased pretreatment serum LDH and ALP levels are poor prognostic factors for NPC.

Is prophylactic neck irradiation indicated for patients with cN0 adenoid cystic carcinoma of the paranasal sinuses?

PURPOSE: To study the prevalence of nodal metastases in sinonasal adenoid cystic carcinoma (SNACC) and to evaluate whether prophylactic neck irradiation (PNI) should be performed in patients with clinical N0 (cN0) disease. PATIENTS AND METHODS: Between April 1992 and November 2020, 166 patients with SNACC who had undergone radiotherapy at our department were retrospectively analyzed. The median follow-up time was 71.3 months. RESULTS: Among 166 cases of SNACC, a total of 13 (7.8%) had retropharyngeal or cervical nodal metastasis and 93% (12/13) cases occurred in patients with advanced T stage (T3-T4). Levels VIIa, Ib, and IIa were the most common sites of initial nodal involvement. Only 1.2% (2/166) of patients presented late neck recurrence. Lymph node metastasis independently predicted a poor progression-free survival (PFS) (P = 0.017) but had no impact on overall survival (OS) (P = 0.38). PNI was performed on 36% (55/153) of cN0 patients. The OS (P = 0.42), PFS (P = 0.59), nodal recurrence-free survival (NRFS) (P = 0.46) and distant metastasis-free survival (DMFS) (P = 0.63) rates showed no significant difference between cases with and without PNI. Furthermore, cN0 patients with T4b (P = 0.53; P = 0.61), tumor origin from maxillary sinus (P = 0.55; P = 0.53) or nasopharynx involvement (P = 0.56; P = 0.60) showed no extended OS or PFS associated with PNI. CONCLUSIONS: Regardless of the T stage or the site of origin, prophylactic neck irradiation (PNI) for cN0 patients did not provide any benefit on OS and PFS, suggesting that its application on such patients is not warranted unless there is clinical suspicion.

A Signature of N6-methyladenosine Regulator-Related Genes Predicts Prognoses and Immune Responses for Head and Neck Squamous Cell Carcinoma.

This study aimed to construct a signature of N6-methyladenosine (m6A) regulator-related genes that could be used for the prognosis of head and neck squamous cell carcinoma (HNSCC) and to clarify the molecular and immune characteristics and benefits of immune checkpoint inhibitor (ICI) therapy using the prognostic signature to define the subgroups of HNSCC. This study showed that eighteen m6A regulators were abnormally expressed in the Cancer Genome Atlas (TCGA) HNSCC tissues compared with those in normal tissues. We constructed a signature of 12 m6A regulator-related genes using the Cox risk model, combined with the least absolute shrinkage and selection operator (Lasso) variable screening algorithm. Based on the median of the signature risk score, the patients were divided into high- and low-risk groups. The Kaplan-Meier survival analyses showed that patients with high-risk scores demonstrated poorer overall survival (OS) than those with low-risk scores based on TCGA-HNSCC data (p <0.001). The OS of high-risk patients was significantly worse than that of low-risk patients in the GSE65858 (p <0.001) and International Cancer Genome Consortium (ICGC) oral cancer cohorts (p = 0.0089). Furthermore, immune infiltration analyses showed that 8 types of immune cell infiltration showed highly significant differences between the two risk groups (p <0.001). In the Imvigor210CoreBiologies dataset of patients who received ICIs, the objective response rate (ORR) of the low-risk group (32%) was significantly higher than that of the high-risk group (13%). Additionally, patients in the high-risk group presented with a more significant adverse OS than that of the low-risk group (p = 0.00032). GSE78220 also showed that the ORR of the low-risk group (64%) was higher than that of the high-risk group (43%) and the OS of low-risk patients was better than that of high-risk patients (p = 0.0064). The constructed prognostic signature, based on m6A regulator-related genes, could be used to effectively distinguish between prognoses for HNSCC patients. The prognostic signature was found to be related to the immune cell infiltration of HNSCC; it might help predict the responses and prognoses of ICIs during treatment.

A Prospective Study on Defining the Indications of Prophylactic Level IB Radiotherapy in Nasopharyngeal Carcinoma Based on a Risk Score Model.

OBJECTIVE: The aim of the study was to investigate clinical evidence for defining the indications of prophylactic level IB radiotherapy (RT) in nasopharyngeal carcinoma (NPC). METHODS: We conducted a phase 2 prospective study in 116 newly diagnosed patients with NPC treated by intensity-modulated RT. Whether level IB was irradiated is based on the risk score model (RSM). Two groups based on RSM were obtained: low risk and high risk. Omission of level IB irradiation was conducted in the low-risk group, otherwise level IB was contoured as part of the treatment target. Grade 2 or worse xerostomia at 12 months was assessed by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-H&N35 questionnaire. RESULTS: At a median follow-up of 16 months (range, 1-26 months), none of the patients developed failures at level IB. The 1-year overall survival, locoregional recurrence-free survival, and distant metastasis-free survival rates were 98.3%, 97.2%, and 95.8%, respectively. At 12 months xerostomia side-effects were reported in 90 of 116 alive patients; grade 2 or worse xerostomia at 12 months was significantly lower in the low-risk group than in the high-risk group. CONCLUSION: Omission of level IB irradiation was feasible for patients with low-risk IB lymph nodes metastasis.

Is a high-risk clinical target volume required? Evaluation of the dosimetric feasibility based on T staging.

Background: Clinical target delineation is a primary focus in the field of radiotherapy. This study aimed to investigate whether high-risk clinical target volume can be removed in nasopharyngeal carcinoma patients with different T stages. Materials and methods: We designed a test plan without the high-risk clinical target volume for 111 nasopharyngeal carcinoma patients and further compared the test plans with the treatment plans in the parameters of planning target volumes and the radiation dose to normal organs. Results: Our data showed that when high-risk clinical target volume was abnegated, target coverage, conformity indices, and homogeneity indices of planning target volumes and doses of normal organs were not influenced in the T4 nasopharyngeal carcinoma patients, and more than 95% of the high-risk planning target volume area could still be covered by the 60 Gy dose line. However, only some T1-3 patients achieved the ideal dose coverage, and even fewer after induction chemotherapy (62.8% vs. 41.2%, p = 0.018). Gross tumor volume was positively correlated with the target coverage of the original high-risk planning target volume in the test-plan (p = 0.0001). Gross tumor volume can be used to predict whether the target coverage of high-risk planning target volume is more than 95% (area under the curve = 0.868). Conclusion: Omitting high risk clinical target volume can be considered in patients with T4 nasopharyngeal carcinoma according to physical evaluations. However, this approach is only suitable for a specific subset of T1-3 patients.

Corrigendum: LCN2 Is a Potential Biomarker for Radioresistance and Recurrence in Nasopharyngeal Carcinoma.

[This corrects the article DOI: 10.3389/fonc.2020.605777.].

Upregulated osteoprotegerin expression promotes lung cancer cell invasion by increasing miR-20a expression.

Osteoprotegerin (OPG) is a member of the tumor necrosis factor receptor superfamily and a major regulatory factor in osteoclast development. OPG has been previously associated with the malignant behavior of various types of cancer, particularly that of cancer metastasis. However, information on the link between the expression profile of OPG and lung cancer metastasis remained elusive. In the present study, the expression levels of OPG in the serum samples of patients with non-small cell lung cancer (NSCLC) was measured using ELISA. The expression of miRNAs was assessed using reverse transcription-quantitative PCR. A549 or H3122 cell invasion was assessed using Transwell invasion assays. The effect of OPG on the invasiveness of lung cancer cells was evaluated using an experimental mouse lung metastasis model. OPG expression was found to be upregulated in the serum of patients with NSCLC compared with that in healthy individuals. The serum levels of OPG in patients with distant metastasis were observably higher compared with those in patients without metastasis. Functionally, overexpression of OPG in NSCLC cells markedly promoted cell invasion. Mechanistically, increased expression of OPG resulted in upregulation of microRNA (miR)-20a in NSCLC cells. Furthermore, miR-20a promoted NSCLC cell invasion, whilst miR-20a inhibition partially abrogated the effect of OPG on NSCLC cell invasion. Taken together, the present results demonstrated that the OPG/miR-20a axis serve an important role in lung cancer metastasis, which potentially provide an additional novel target for lung cancer treatment.

High Expression of Hyaluronan-Mediated Motility Receptor Predicts Adverse Outcomes: A Potential Therapeutic Target for Head and Neck Squamous Cell Carcinoma.

Background: Several studies have shown that the hyaluronan-mediated motility receptor (HMMR) is overexpressed in various cancers and could be a potential prognostic factor. However, further research is still required to determine the prognostic value and potential function of HMMR in head and neck squamous cell carcinoma (HNSCC). Materials and Methods: Transcriptomic expression data were collected from the Cancer Genome Atlas database (TCGA) and Gene Expression Omnibus and the differences in HMMR expression between normal and tumor tissues were analyzed. The correlation between the methylation level of HMMR and its mRNA expression was analyzed via cBioPortal. Additionally, the data obtained from TCGA was analyzed with MethSurv to determine the prognostic value of the HMMR methylation levels in HNSCC. Gene set enrichment analysis (GSEA) and single sample GSEA (ssGSEA) were used to explore the potential biological functions of HMMR. Results: HMMR was highly expressed in HNSCC tumor tissue compared to normal tissue (p < 0.001). Multivariate analysis (MAV) showed that high HMMR mRNA expression was an independent prognostic factor of overall survival (OS) in TCGA (HR = 1.628, 95% CI: 1.169-2.266, p = 0.004) and GSE41613 data (HR = 2.238, p = 0.013). The methylation level of HMMR negatively correlated with the HMMR expression (R = -0.12, p < 0.001), and patients with low HMMR methylation had worse OS than patients with high methylation (p < 0.001). GSEA found that HMMR expression was associated with the KARS, EMT, and G2M checkpoint pathways, as well as the interferon-gamma and interferon-alpha responses, whereas ssGSEA showed that HMMR expression positively correlated with the infiltration level of Th2 cells. MAV confirmed that high HMMR protein expression was an inferior independent factor for OS (HR = 2.288, p = 0.045) and progression-free survival (HR = 2.247, p = 0.038) in 70 HNSCC. Conclusions: This study demonstrated that the upregulation of HMMR mRNA and protein in HNSCC is a biomarker for poor prognosis. The biological functions of HMMR are potentially related to the KARS, EMT, and G2M checkpoint pathways, as well as the interferon-gamma and interferon-alpha responses. These findings help to elucidate the role of HMMR in carcinogenesis and lay a foundation for further study.

SEC61G overexpression and DNA amplification correlates with prognosis and immune cell infiltration in head and neck squamous cell carcinoma.

BACKGROUND: The SEC61 translocon gamma subunit (SEC61G) is a component of the SEC61 complex, which import protein into the endoplasmic reticulum. However, the correlation between SEC61G and disease prognosis in head and neck squamous cell carcinoma (HNSCC) remains unclear. METHODS: SEC61G expression was analyzed using publicly available datasets. The association between SEC61G and disease prognosis was evaluated. SEC61G methylation and copy number variation were investigated and gene set enrichment analysis and gene ontology analyses identified SEC61G-associated functions. We also investigated the correlation between SEC61G and immune cell infiltration. Finally, immunohistochemistry was used to detect SEC61G expression in oropharyngeal carcinoma. RESULTS: SEC61G was overexpressed in pan-cancers, including HNSCC, and negatively correlated with overall survival (OS) (p < 0.001 for TCGA-HNSCC and p = 0.019 for GSE65858). Moreover, SEC61G was an independent prognostic factor for OS in TCGA and GSE65858 [hazard ratio (HR) = 1.80, 95% CI: 1.35-2.39, p < 0.001; HR = 1.87, 95% CI: 1.14-3.07, p = 0.013, respectively). SEC61G DNA amplification (9.66% of patients) was significantly associated with poor OS (p = 0.034). SEC61G overexpression and DNA amplification negatively correlated with B cell (p < 0.001), CD8+ T cell (p < 0.001), CD4+ T cell (p < 0.001), macrophage (p < 0.05), neutrophil (p < 0.001), and dendritic cell infiltration (p < 0.001). Among patients with metastatic urothelial cancer received atezolizumab, patients with high SEC61G expression had an inferior OS (p = 0.006). Furthermore, SEC61G protein expression was also an independent prognostic factor of OS (HR = 2.46, 95% CI: 1.15-5.28, p = 0.021) and progression-free survival (HR = 2.82, 95% CI: 1.36-5.85, p = 0.005) for oropharyngeal cancer. CONCLUSIONS: SEC61G is overexpressed in HNSCC and is an independent prognostic factor for OS. SEC61G DNA amplification contributes to overexpression and poor outcome. Interestingly, SEC61G correlates with immune cell infiltration in HNSCC. These findings suggest that SEC61G is a potential broad-spectrum biomarker for prognosis in HNSCC.