MicroRNA-575 targets Derlin 1 to regulate proliferation, migration and invasion of human thyroid cancer cells.

Introduction: This study was undertaken to examine the expression of miR-575 in thyroid cancer tissues and to explore its therapeutic potential. Material and methods: Expression analysis was carried out by qRT-PCR. The MTT assay was used for cell viability. DAPI and annexin V/PI assays were used to detect apoptosis. Wound healing and Transwell assays were used for cell migration and invasion respectively. Western blot analysis was used to determine the expression of proteins. Results: The results showed significant downregulation of miR-575 in thyroid cancer tissues and cell lines. The role of miR-575 was deciphered by overexpression of miR-575 in MDA-T32 and MDA-T68 thyroid cancer cells. The results showed that overexpression of miR-575 caused significant inhibition of the proliferation of the MDA-T32 and MDA-T68 cells via induction of apoptotic cell death. The expression of Bax was also enhanced while that of Bax was decreased upon miR-575 overexpression in MDA-T32 and MDA-T68 cells. Additionally, miR-575 overexpression inhibited the migration and invasion of the MDA-T32 and MDA-T68 thyroid cancer cells. Bioinformatic approaches and the dual luciferase assay indicated Derlin 1 (DERL1) to be the potential target of miR-575 in thyroid cancer. DERL1 was significantly upregulated in thyroid cancer tissues and cell lines and overexpression of miR-575 caused suppression of DERL1 in MDA-T68 cells. Silencing of DERL1 inhibited the proliferation of the MDA-T68 cells while overexpression of DERL1 could abolish the effects of miR-575 overexpression on the proliferation of MDA-T68 thyroid cancer cells. Conclusions: miR-575 may be used as a therapeutic target for thyroid cancer treatment.

m6A-enriched lncRNA LINC00839 promotes tumor progression by enhancing TAF15-mediated transcription of amine oxidase AOC1 in nasopharyngeal carcinoma.

Dysregulation of long noncoding RNAs (lncRNAs) contributes to tumorigenesis by modulating specific cancer-related pathways, but the roles of N6-methyladenosine (m6A)-enriched lncRNAs and underlying mechanisms remain elusive in nasopharyngeal carcinoma (NPC). Here, we reanalyzed the previous genome-wide analysis of lncRNA profiles in 18 pairs of NPC and normal tissues as well as in ten paired samples from NPC with or without post-treatment metastases. We discerned that an oncogenic m6A-enriched lncRNA, LINC00839, which was substantially upregulated in NPC and correlated with poor clinical prognosis, promoted NPC growth and metastasis both in vitro and in vivo. Mechanistically, by using RNA pull-down assay combined with mass spectrometry, we found that LINC00839 interacted directly with the transcription factor, TATA-box binding protein associated factor (TAF15). Besides, chromatin immunoprecipitation and dual-luciferase report assays demonstrated that LINC00839 coordinated the recruitment of TAF15 to the promoter region of amine oxidase copper-containing 1 (AOC1), which encodes a secreted glycoprotein playing vital roles in various cancers, thereby activating AOC1 transcription in trans. In this study, potential effects of AOC1 in NPC progression were first proposed. Moreover, ectopic expression of AOC1 partially rescued the inhibitory effect of downregulation of LINC00839 in NPC. Furthermore, we showed that silencing vir-like m6A methyltransferase-associated (VIRMA) and insulin-like growth factor 2 mRNA-binding proteins 1 (IGF2BP1) attenuated the expression level and RNA stability of LINC00839 in an m6A-dependent manner. Taken together, our study unveils a novel oncogenic VIRMA/IGF2BP1-LINC00839-TAF15-AOC1 axis and highlights the significance and prognostic value of LINC00839 expression in NPC carcinogenesis.

VIRMA promotes nasopharyngeal carcinoma, tumorigenesis, and metastasis by upregulation of E2F7 in an m6A-dependent manner.

The N6-methyladenosine (m6A) modification possesses new and essential roles in tumor initiation and progression by regulating mRNA biology. However, the role of aberrant m6A regulation in nasopharyngeal carcinoma (NPC) remains unclear. Here, through comprehensive analyses of NPC cohorts from the GEO database and our internal cohort, we identified that VIRMA, an m6A writer, is significantly upregulated in NPC and plays an essential role in tumorigenesis and metastasis of NPC, both in vitro and in vivo. High VIRMA expression served as a prognostic biomarker and was associated with poor outcomes in patients with NPC. Mechanistically, VIRMA mediated the m6A methylation of E2F7 3'-UTR, then IGF2BP2 bound, and maintained the stability of E2F7 mRNA. An integrative high-throughput sequencing approach revealed that E2F7 drives a unique transcriptome distinct from the classical E2F family in NPC, which functioned as an oncogenic transcriptional activator. E2F7 cooperated with CBFB-recruited RUNX1 in a non-canonical manner to transactivate ITGA2, ITGA5, and NTRK1, strengthening Akt signaling-induced tumor-promoting effect.

Thyroid dysfunction in Chinese nasopharyngeal carcinoma after anti-PD-1 therapy and its association with treatment response.

BACKGROUND: Programmed cell death protein-1 (PD-1) blockade therapies have demonstrated efficacy in nasopharyngeal carcinoma (NPC). Thyroid dysfunction is among the most common immune-related adverse events. This study aimed to explore the clinical pattern of thyroid dysfunction and its relationship with survival marker in nonmetastatic NPC after immunotherapy. METHODS: From January 1, 2019, to December 31, 2021, 165 pairs of nonmetastatic NPC patients (165 with and 165 without anti-PD-1 immunotherapy) matched by the propensity score matching method were included in this study. Thyroid function was assessed retrospectively before the first treatment and during each immunotherapy cycle. RESULTS: The spectrum of thyroid dysfunction was different between the immunotherapy and control groups (P < 0.001). Compared with the control group, patients in the immunotherapy group developed more hypothyroidism (14.545% vs. 7.273%), less hyperthyroidism (10.909% vs. 23.636%), and a distinct pattern, biphasic thyroid dysfunction (3.030% vs. 0%). Immunotherapy also accelerates the onset of hypothyroidism, which was earlier with a median onset time difference of 32 days (P < 0.001). Patients who acquired thyroid dysfunction during immunotherapy had better complete biological response to treatment (OR, 10.980; P = 0.042). CONCLUSIONS: For nonmetastatic NPC, thyroid dysfunction was associated with better response to treatment in immunotherapy but not in routine treatment. Thyroid function could be used as a predictor for survival and should be under regular and intensive surveillance in clinical practice of anti-PD-1 immunotherapy for nonmetastatic NPC.

Prognostic models for early and late tumor progression prediction in nasopharyngeal carcinoma: An analysis of 8292 endemic cases.

OBJECTIVES: The time for posttreatment tumor progression differs between nasopharyngeal carcinoma (NPC) patients. Herein, we established effective nomograms for predicting early tumor progression (ETP) and late tumor progression (LTP) in NPC patients. METHODS: We retrospectively enrolled 8292 NPC patients (training cohort: n = 6219; validation cohort: n = 2073). The ELP and LTP were defined as the time to tumor progression ≤24 and >24 months after treatment, respectively. RESULTS: The ETP and LTP accounted for 52.6 and 47.4% of the total patient cohort, respectively. Patients who developed ETP had markedly worse overall survival (OS) versus patients who suffered from LTP (5-year OS: 26.2% vs. 59.7%, p < 0.001). Further, we identified 10/6 predictive factors significantly associated with ETP/LTP via logistic regression analyses. These indicators were used separately to construct two predictive nomograms for ETP and LTP. In the training group, the ETP nomogram [Harrell Concordance Index (C-index) value: 0.711 vs. 0.618; p < 0.001] and LTP nomogram (C-index value: 0.701 vs. 0.612; p < 0.001) were significantly superior for risk stratification than the TNM staging. These results were supported in the validation group with a C-index value of 0.753 and 0.738 for the ETP and LTP nomograms, respectively. High-risk patients defined by ETP/LTP nomograms had shorter progression-free survival than low-risk patients (all p < 0.001). CONCLUSION: The established nomograms can help in ELP or LTP risk stratification for NPC patients. Our current results might also provide insights into individualized treatment decisions and designing surveillance strategies for NPC patients.

Intraductal papillary carcinoma of breast with invasion: A nomogram and survival from the analysis of the SEER database.

BACKGROUND: Intraductal papillary carcinoma (IPC) with invasion is a rare type of breast cancer. There have been few studies on its prognosis, and a nomogram that predicts the prognosis of the disease has not been described to date. METHODS: Patients who were diagnosed with invasive IPC were screened from the Surveillance, Epidemiology, and End Results (SEER) database. The screened patients were randomly divided into a training cohort and a verification cohort at 7:3. A Cox proportional hazard regression model was performed to analyze the effects of different variables on the risk of death in invasive IPC. A nomogram was constructed to quantify the possibility of death. The concordance index (C-index), calibration plots, receiver operating characteristic (ROC) curves, and decision curves analysis (DCA) were used to verify the proposed model. RESULTS: We included a total of 803 patients diagnosed with invasive IPC, including 563 patients in the training cohort and 240 patients in the validation cohort. The median follow-up times in the training cohort and validation cohort were 63 months (range, 2-155 months) and 61 months (range, 1-154 months), respectively. For all patients, the probability of death with invasive IPC was 1.4% within 5 years and 5.4% within 10 years. In multivariate analysis, sex, race, tumor size, lymph node status, type of treatment, and chemotherapy were related to the prognosis of invasive IPC. We constructed a nomogram to predict the possibility of death in patients with invasive IPC. CONCLUSION: Patients with invasive IPC had a high survival rate. The proven nomogram was helpful to both patients and clinical decision makers.

Neutralization Epitopes in Trimer and Pentamer Complexes Recognized by Potent Cytomegalovirus-Neutralizing Human Monoclonal Antibodies.

Human cytomegalovirus (HCMV) infects 36% to almost 100% of adults and causes severe complications only in immunocompromised individuals. HCMV viral surface trimeric (gH/gL/gO) and pentameric (gH/gL/UL128/UL130/UL131A) complexes play important roles in HCMV infection and tropism. Here, we isolated and identified a total of four neutralizing monoclonal antibodies (MAbs) derived from HCMV-seropositive blood donors. Based on their reactivity to HCMV trimer and pentamer, these MAbs can be divided into two groups. MAbs PC0012, PC0014, and PC0035 in group 1 bind both trimer and pentamer and neutralize CMV by interfering with the postattachment steps of CMV entering into cells. These three antibodies recognize antigenic epitopes clustered in a similar area, which are overlapped by the epitope recognized by the known neutralizing antibody MSL-109. MAb PC0034 in group 2 binds only to pentamer and neutralizes CMV by blocking the binding of pentamer to cells. Epitope mapping using pentamer mutants showed that amino acid T94 of the subunit UL128 and K27 of UL131A on the pentamer are key epitope-associated residues recognized by PC0034. This study provides new evidence and insight information on the importance of the development of the CMV pentamer as a CMV vaccine. In addition, these newly identified potent CMV MAbs can be attractive candidates for development as antibody therapeutics for the prevention and treatment of HCMV infection. IMPORTANCE The majority of the global population is infected with HCMV, but severe complications occur only in immunocompromised individuals. In addition, CMV infection is a major cause of birth defects in newborns. Currently, there are still no approved prophylactic vaccines or therapeutic monoclonal antibodies (MAbs) for clinical use against HCMV infection. This study identified and characterized a panel of four neutralizing MAbs targeting the HCMV pentamer complex with specific aims to identify a key protein(s) and antigenic epitopes in the HCMV pentamer complex. The study also explored the mechanism by which these newly identified antibodies neutralize HCMV in order to design better HCMV vaccines focusing on the pentamer and to provide attractive candidates for the development of effective cocktail therapeutics for the prevention and treatment of HCMV infection.

Contribution of insurance status to the association between marital status and cancer-specific survival: a mediation analysis.

OBJECTIVES: To evaluate the extent to which marriage influences cancer-specific survival (CSS) by influencing the insurance status among patients with common solid cancers and the feasibility of reducing the survival gap caused by marriage by increasing private insurance coverage for unmarried patients. SETTING: A retrospective cohort study with patients retrieved from the Surveillance, Epidemiology and End Results programme. PARTICIPANTS: Patients with nine common solid cancers diagnosed between 2007 and 2016 were included. Patients were excluded if their marital status, insurance status, socioeconomical status, stage or cause of death was unavailable, if survival time was less than 1 month, or if they were younger than 18 years at the time of diagnosis. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was CSS, which was compared between married and unmarried individuals. Mediation analyses were conducted to determine the contribution of insurance status to the association between marriage and CSS. RESULTS: Married patients had better CSS than those unmarried (time ratio 1.778; 95% CI 1.758 to 1.797). Private health insurance was a key factor mediating the association between marital status and CSS (proportion mediated (PM), 17%; 95% CI 17% to 17.1%). The PM ranges from 10.7% in prostate cancer to 20% in kidney cancer. The contribution of private insurance to the association between marital status and CSS was greater among women than among men (PM 18.5% vs 16.7%). The mediating effect of private insurance was the greatest for the comparison between married and separated individuals (PM 25.6%; 95% CI 25.3% to 25.8%) and smallest for the comparison between married and widowed individuals (PM 11.0%; 95% CI 10.9% to 11.1%). CONCLUSIONS: 17% of the marital disparities in CSS are mediated by private insurance coverage. Increasing private insurance coverage for unmarried patients may reduce the survival gap related to marital status and sex. However, it is unclear whether better publicly funded insurance would have the same effect.

In Situ Preservation of Parathyroid Gland With Vasculature for Papillary Thyroid Carcinoma Is Associated With Higher PTH Levels After Total Thyroidectomy.

PURPOSE: To evaluate the impact of parathyroid gland vasculature preservation in-situ technique (PGVPIST) on postoperative parathyroid hormone (PTH) and calcium plasma levels in thyroid patients undergoing total thyroidectomy for papillary thyroid carcinoma (PTC). STUDY DESIGN: Retrospective cohort study. METHODS: Patients with PTC who underwent total thyroidectomy by either the conventional technique (group 1, January 2019 to January 2020) or PGVPIST (group 2, January 2020 to January 2021) were compared. Postoperative blood calcium levels and PTH levels were assessed in these groups. RESULTS: Totally 149 patients with consecutive PTC underwent total thyroidectomy, including 60 patients in group 1 and 89 patients in group 2. Postoperative serum calcium levels in group 1 were insignificantly lower than in group 2 at day 1 (2.18 ± 0.02 vs 2.15 ± 0.01 mmol/L) and day 30 (2.27 ± 0.02 vs 2.38 ± 0.11) after surgery. But postoperative serum PTH levels in group 1 were significantly lower than that in group 2 at day 1 (23.68 ± 2.54 vs 31.46 ± 2.11 pg/mL) and day 30 (45.63 ± 3.21 vs 55.65 ± 2.89 pg/mL) after surgery. CONCLUSION: Parathyroid gland vasculature preservation in-situ technique for PTC is associated with higher PTH level after total thyroidectomy. The parathyroid gland vasculature mostly strongly adheres with adjacent thyroid parenchyma. Therefore, deferred processing of tiny thyroid parenchyma of parathyroid gland vessels is essential to prevent devascularization.

Development of a Nomogram Model for Treatment of Elderly Patients with Locoregionally Advanced Nasopharyngeal Carcinoma.

(1) Purpose: This study aims to explore risk-adapted treatment for elderly patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) according to their pretreatment risk stratification and the degree of comorbidity. (2) Methods: A total of 583 elderly LA-NPC patients diagnosed from January 2011 to January 2018 are retrospectively studied. A nomogram for disease-free survival (DFS) is constructed based on multivariate Cox regression analysis. The performance of the model is evaluated by using the area under the curve (AUC) of the receiver operating characteristic curve and Harrell concordance index (C-index). Then, the entire cohort is divided into different risk groups according to the nomogram cutoff value determined by X-tile analysis. The degree of comorbidities is assessed by the Charlson Comorbidity Index (CCI). Finally, survival rates are estimated and compared by the Kaplan-Meier method and the log-rank test. (3) Results: A nomogram for DFS is constructed with T/N classification, Epstein-Barr virus DNA and albumin. The nomogram shows well prognostic performance and significantly outperformed the tumor-node-metastasis staging system for estimating DFS (AUC, 0.710 vs. 0.607; C-index, 0.668 vs. 0.585; both p < 0.001). The high-risk group generated by nomogram has significantly poorer survival compared with the low-risk group (3-year DFS, 76.7% vs. 44.6%, p < 0.001). For high-risk patients with fewer comorbidities (CCI = 2), chemotherapy combined with radiotherapy is associated with significantly better survival (p < 0.05) than radiotherapy alone. (4) Conclusion: A prognostic nomogram for DFS is constructed with generating two risk groups. Combining risk stratification and the degree of comorbidities can guide risk-adapted treatment for elderly LA-NPC patients.

Liquid biopsy posttreatment surveillance in endemic nasopharyngeal carcinoma: a cost-effective strategy to integrate circulating cell-free Epstein-Barr virus DNA.

BACKGROUND: The optimal posttreatment surveillance strategy for nasopharyngeal carcinoma (NPC) remains unclear. Circulating cell-free Epstein-Barr virus (cfEBV) DNA has been recognized as a promising biomarker to facilitate early detection of NPC recurrence. Therefore, we aim to determine whether integrating circulating cfEBV DNA into NPC follow-up is cost-effective. METHODS: For each stage of asymptomatic nonmetastatic NPC patients after complete remission to primary NPC treatment, we developed a Markov model to compare the cost-effectiveness of the following surveillance strategies: routine follow-up strategy, i.e., (1) routine clinical physical examination; routine imaging strategies, including (2) routine magnetic resonance imaging plus computed tomography plus bone scintigraphy (MRI + CT + BS); and (3) routine 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT); cfEBV DNA-guided imaging strategies, including (4) cfEBV DNA-guided MRI + CT + BS and (5) cfEBV DNA-guided PET/CT. Clinical probabilities, utilities, and costs were derived from published studies or databases. Sensitivity analyses were performed. RESULTS: For all disease stages, cfEBV DNA-guided imaging strategies demonstrated similar survival benefits but were considerably more economical than routine imaging strategies. They only required approximately one quarter of the number of imaging studies compared with routine imaging strategies to detect one recurrence. Specifically, cfEBV DNA-guided MRI + CT + BS was most cost-effective for stage II (incremental cost-effectiveness ratio [ICER] $57,308/quality-adjusted life-year [QALY]) and stage III ($46,860/QALY) patients, while cfEBV DNA-guided PET/CT was most cost-effective for stage IV patients ($62,269/QALY). However, routine follow-up was adequate for stage I patients due to their low recurrence risk. CONCLUSIONS: The cfEBV DNA-guided imaging strategies are effective and cost-effective follow-up methods in NPC. These liquid biopsy-based strategies offer evidence-based, stage-specific surveillance modalities for clinicians and reduce disease burden for patients.

Oestrogen receptor alpha in papillary thyroid carcinoma: association with clinical features and BRAFV600E mutation.

BACKGROUND: Papillary thyroid cancer cells can express oestrogen receptor alpha, which is encoded by the ESR1 gene and may bind to oestrogen to induce the occurrence and development of papillary thyroid cancer. The BRAFV600E mutation is also an important biomarker for the occurrence and progression of papillary thyroid cancer. However, the association between the BRAFV600E mutation and oestrogen receptor alpha expression has not been identified. This study aims to investigate the association between ESR1 expression and the BRAFV600E mutation and its clinical significance. METHODS: Oestrogen receptor alpha and BRAFV600E proteins were detected by immunohistochemical staining of formalin-fixed paraffin-embedded thyroid tissues from 1105 patients with papillary thyroid cancer at our institution. Messenger RNA expression counts of ESR1 and clinicopathologic information were obtained from The Cancer Genome Atlas database. RESULTS: Oestrogen receptor alpha protein expression was significantly associated with BRAFV600E protein. The positive rate of oestrogen receptor alpha protein in papillary thyroid cancer patients was significantly higher in males, younger patients and patients with the multifocal type. In papillary thyroid cancer patients with positive BRAFV600E protein, oestrogen receptor alpha expression was significantly correlated with central lymph node metastasis. Data from the The Cancer Genome Atlas database also suggested that the ESR1 messenger RNA level was associated with the BRAFV600E mutation. Furthermore, classification analysis performed according to a tree-based classification method demonstrated that higher ESR1 messenger RNA expression indicated poorer overall survival in papillary thyroid cancer patients with the BRAFV600E mutation. CONCLUSIONS: The percentage of BRAFV600E mutations is increased in patients with higher ESR1 messenger RNA levels, and the BRAFV600E protein might be co-expressed with oestrogen receptor alpha, which could be an indicator of cervical lymph node metastasis and poor overall survival in patients with papillary thyroid cancer.

Astragaloside IV inhibits cell proliferation and metastasis of breast cancer via promoting the long noncoding RNA TRHDE-AS1.

Astragaloside IV (ASV), which has several pharmacological abilities, shows potential therapeutic effects on certain cancers by regulating the expression of long noncoding RNA (lncRNA). However, the anticancer role that ASV plays by regulating lncRNAs in breast cancer remains unknown. In this study, we first demonstrated that the lncRNA of TRHDE antisense RNA 1 (TRHDE-AS1) was downregulated in breast cancer tissues and cells. Low TRHDE-AS1 expression is associated with poor outcomes in patients with breast cancer and potentially contributes to the aggressive tumor biology of breast cancer. Furthermore, ASV significantly increased TRHDE-AS1 expression in a dose- and time-dependent manner in breast cancer cells. By upregulating TRHDE-AS1, ASV repressed breast cancer cell growth and metastasis both in vitro and in vivo. Taken together, our data indicated that TRHDE-AS1 participates in the anticancer role of ASV in breast cancer, which provides evidence for the application of ASV for breast cancer therapy.

Development and validation of a web-based calculator to predict individualized conditional risk of site-specific recurrence in nasopharyngeal carcinoma: Analysis of 10,058 endemic cases.

BACKGROUND: Conditional survival (CS) provides dynamic prognostic estimates by considering the patients existing survival time. Since CS for endemic nasopharyngeal carcinoma (NPC) is lacking, we aimed to assess the CS of endemic NPC and establish a web-based calculator to predict individualized, conditional site-specific recurrence risk. METHODS: Using an NPC-specific database with a big-data intelligence platform, 10,058 endemic patients with non-metastatic stage I-IVA NPC receiving intensity-modulated radiotherapy with or without chemotherapy between April 2009 and December 2015 were investigated. Crude CS estimates of conditional overall survival (COS), conditional disease-free survival (CDFS), conditional locoregional relapse-free survival (CLRRFS), conditional distant metastasis-free survival (CDMFS), and conditional NPC-specific survival (CNPC-SS) were calculated. Covariate-adjusted CS estimates were generated using inverse probability weighting. A prediction model was established using competing risk models and was externally validated with an independent, non-metastatic stage I-IVA NPC cohort undergoing intensity-modulated radiotherapy with or without chemotherapy (n = 601) at another institution. RESULTS: The median follow-up of the primary cohort was 67.2 months. The 5-year COS, CDFS, CLRRFS, CDMFS, and CNPC-SS increased from 86.2%, 78.1%, 89.8%, 87.3%, and 87.6% at diagnosis to 87.3%, 87.7%, 94.4%, 96.0%, and 90.1%, respectively, for an existing survival time of 3 years since diagnosis. Differences in CS estimates between prognostic factor subgroups of each endpoint were noticeable at diagnosis but diminished with time, whereas an ever-increasing disparity in CS between different age subgroups was observed over time. Notably, the prognoses of patients that were poor at diagnosis improved greatly as patients survived longer. For individualized CS predictions, we developed a web-based model to estimate the conditional risk of local (C-index, 0.656), regional (0.667), bone (0.742), lung (0.681), and liver (0.711) recurrence, which significantly outperformed the current staging system (P < 0.001). The performance of this web-based model was further validated using an external validation cohort (median follow-up, 61.3 months), with C-indices of 0.672, 0.736, 0.754, 0.663, and 0.721, respectively. CONCLUSIONS: We characterized the CS of endemic NPC in the largest cohort to date. Moreover, we established a web-based calculator to predict the CS of site-specific recurrence, which may help to tailor individualized, risk-based, time-adapted follow-up strategies.

Protective effect of gastrodin on peripheral neuropathy induced by anti-tumor treatment with vincristine in rat models.

Cancer is a common disease threatening human health, chemotherapy is widely used in clinical treatment of cancer, but chemotherapy-induced peripheral neuropathy (CIPN) has a relevant impact on life quality of cancer patients. Administration of gastrodin can relieve chronic pain to cancer patients with CIPN and attenuated the inflammatory response by reducing the expression of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). However, its exact molecular mechanisms remain unclear. In this study, we established an animal model of CIPN using Walker-256 breast cancer cell and vincristine. We found that the mechanical and thermal pain threshold of rats was decreased with treatment of vincristine. Using gastrodin could restore the mechanical and thermal threshold without interfering anti-tumor effect of vincristine. Gastrodin relieved CIPN by inhibiting activation of spinal microglia through Fractalkine (CX3CL1) and its receptor CX3CR1, then inhibited P38/mitogen-activated protein kinase (MAPK) signaling pathway and reduced the expression of inflammatory factor TNF-α and interleukin-1ß (IL-1ß). Taking together, our study demonstrated that gastrodin is a potential drug for the treatment of CIPN and likely to improve cancer patient's life quality.

LncRNA DDX11-AS1 accelerates hepatocellular carcinoma progression via the miR-195-5p/MACC1 pathway.

INTRODUCTION AND AIM: Long non-coding RNA (lncRNA) has been shown to be a vital regulator of cancer progression, including hepatocellular carcinoma (HCC). However, the role of DEAD/H box protein 11 antisense RNA 1 (DDX11-AS1) in HCC remains to be further studied. MATERIAL AND METHODS: The expression levels of DDX11-AS1, miR-195-5p and metastasis-associated in colon cancer-1 (MACC1) were determined by quantitative real-time PCR (qRT-PCR). Cell counting kit-8 (CCK-8), transwell and apoptosis determination assays were used to evaluate cell proliferation, migration, invasion and apoptosis, respectively. Mice xenograft models were constructed to verify the effect of DDX11-AS1 on HCC tumor growth in vivo. Furthermore, lactate production, glucose consumption, ATP level and glucose uptake were detected to assess cell glucose metabolism. The interactions among DDX11-AS1, miR-195-5p and MACC1 were verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Moreover, western blot (WB) analysis was performed to evaluate the protein levels. RESULTS: DDX11-AS1 was upregulated in HCC tissues and cells, and its silencing could inhibit HCC cell proliferation, migration, invasion and glucose metabolism, and promote apoptosis in vitro. Also, DDX11-AS1 knockdown reduced HCC tumor growth in vivo. Besides, DDX11-AS1 could interact with miR-195-5p, and miR-195-5p inhibitor reversed the inhibitory effect of silenced DDX11-AS1 on HCC cell progression. In addition, MACC1 was a target of miR-195-5p, and its overexpression reversed the suppression effect of miR-195-5p on HCC cell progression. CONCLUSION: Our data revealed that DDX11-AS1 could act as an oncogenic regulator in HCC, providing a potential therapeutic target for HCC treatment.

Hsa_circ_0003645 Promotes Breast Cancer Progression by Regulating miR-139-3p/HMGB1 Axis.

BACKGROUND: The aim of the present study was to investigate the effect of over-expressing circular RNA (circ_0003645) on cell functions and its molecular mechanism in breast cancer. METHODS: The expression profile of circ_0003645, breast cancer cell lines, and the transcription levels of circular RNA, miRNA and HMGB1 gene were detected by qRT-PCR. Flow cytometry analysis was manipulated to evaluate cancer cell proliferation and cell apoptosis. The correlation between miR-139p-3p and circular_0003645 or HMGB1 was predicted by GEO, and TCGA was confirmed using the dual-luciferase reporter assay. RESULTS: Circ_0003645 expression was conspicuously increased in both the breast cancer tissues and cell lines. Circ_0003645 knockdown inhibited cell proliferation and induced the apoptosis of breast cancer cells in vitro and in vivo. By sponging miR-139-3p, circ_0003645 promoted the breast cancer cells progression and positively regulated HMGB1 gene. CONCLUSION: Circ_0003645 functions as a ceRNA for miR-139-3p, which could upregulate HMGB1 and further promote cell proliferation in breast cancer.

Long non-coding RNA plasmacytoma variant translocation 1 linked to hypoxia-induced cardiomyocyte injury of H9c2 cells by targeting miR-135a-5p/forkhead box O1 axis.

BACKGROUND: Myocardial infarction occurs due to insufficient (ischemia) blood supply to heart for long time; plasmacytoma variant translocation 1 (PVT1) is a long non-coding RNAs (lncRNAs) involved in the pathogenesis of various diseases, including heart disease; However, few studies have explored its role. The present study evaluated the effects of lncRNA PVT1 on hypoxic rat H9c2 cells. METHODS: Hypoxic injury was examined by measuring cell viability and apoptosis by using cell counting kit-8 activity and flow cytometry assays. Gene expressions after hypoxia were estimated by quantitative real time polymerase chain reaction and the signaling pathway were explored by Western blot analysis. RNA immunoprecipitation and luciferase reporter assays were applied to examine the interactions among genes. Data were analyzed using t-test with one-way or two-way analysis of variance. RESULTS: The lncRNA PVT1 is up-regulated in hypoxia-stressed H9c2 cells and knockdown of PVT1 mitigates hypoxia-induced injury in H9c2 cells. PVT1 acts as a sponge for miR-135a-5p and knockdown of PVT1 attenuated the increased hypoxia-induced injury by up-regulating miR-135a-5p. Forkhead box O1 (FOXO1) was identified as a target of miR-135a-5p, and the expression was negatively regulated by miR-135a-5p. The exploration of the underlying mechanism demonstrated that knockdown of FOXO1 reversed PVT1/miR-135a-5p mediated hypoxia-induced injury in H9c2 cells. CONCLUSIONS: PVT1 plays a crucial role in hypoxia-injured H9c2 cells through sponging miR-135a-5p and then positively regulating FOXO1.

Association of long-chain non-coding RNA GAS5 gene polymorphisms with prostate cancer risk and prognosis in Chinese Han population.

BACKGROUND: To investigate the correlation between growth arrest-specific transcript 5 (GAS5) gene polymorphism and the risk and prognosis of prostate cancer in Chinese Han population. METHODS: Sanger sequencing was used to analyze genotypes at the rs17359906 and rs1951625 loci of the GAS5 gene in 218 prostate cancer patients and 220 healthy controls. The follow-up period was from August 2016 to August 2019, and the relationships between GAS5 gene polymorphisms at the rs17359906 and rs1951625 loci and the recurrence-free survival rate of prostate cancer patients were analyzed. RESULTS: GAS5 A-allele carriers at the rs17359906 locus were 3.44 times more likely to develop prostate cancer than G-allele carriers (95% confidence interval (CI): 2.38-4.96, P < .001). Carriers of the GAS5 A allele at the rs1951625 locus had a 1.40-fold higher risk of prostate cancer than carriers of the G allele (95% CI: 1.05-1.86, P = .027). Plasma prostate-specific antigen (PSA), body mass index (BMI), and rs17359906 and rs1951625 loci were independent risk factors for prostate cancer. GAS5 AA genotype and A-allele carriers (GA + AA) at the rs1951625 locus were significantly correlated with Gleason scores ≤7 (P < .05). GAS5 genes rs17359906 G > A and rs1951625 G > A were associated with high plasma PSA levels. The recurrence-free survival rate of patients with prostate cancer with AA genotype at the rs17359906 locus of GAS5 (66.67%) was significantly lower than that of the GA genotype (76.47%), whereas the GG genotype was the highest (91.96%), and the difference was statistically significant (P = .002). The recurrence-free survival rate of patients with prostate cancer with the AA genotype at the rs1951625 locus of GAS5 (75.00%) was significantly lower than that of the GA genotype (81.82%), whereas the GG genotype was the highest (87.76%) with a statistically significant difference (P = .025). CONCLUSION: GAS5 rs17359906 G > A and rs1951625 G > A are significantly associated with an increased risk of prostate cancer and a reduction in three-year relapse-free survival.