Hypoxia-Specific Metal-Organic Frameworks Augment Cancer Immunotherapy of High-Intensity Focused Ultrasound.

As a noninvasive treatment modality, high-intensity focused ultrasound (HIFU)-induced antitumor immune responses play a vital role in surgery prognosis. However, limited response intensity largely hinders postoperative immunotherapy. Herein, a hypoxia-specific metal-organic framework (MOF) nanosystem, coordinated by Fe3+, hypoxic-activated prodrug AQ4N, and IDO-1 signaling pathway inhibitor NLG919, is developed for the potentiating immunotherapy of HIFU surgery. The loaded AQ4N enhances the photoacoustic imaging effects to achieve accurate intraoperative navigation. Within the HIFU-established severe hypoxic environment, AQ4N is activated sequentially, following which it cooperates with Fe3+ to effectively provoke immunogenic cell death. In addition, potent NLG919 suppresses IDO-1 activity and degrades the immunosuppressive tumor microenvironment aggravated by postoperative hypoxia. In vivo studies demonstrate that the MOF-mediated immunotherapy greatly inhibits the growth of primary/distant tumors and eliminates lung metastasis. This work establishes a robust delivery platform to improve immunotherapy and the overall prognosis of HIFU surgery with high specificity and potency.

Analysis of Prognostic Factors and Cancer-Specific Survival in Patients with Undifferentiated and Dedifferentiated Endometrial Carcinoma Undergoing Various Postoperative Adjuvant Therapies.

Purpose: To investigate prognostic factors affecting cancer-specific survival (CSS) and to analyze the survival outcomes of patients with undifferentiated and dedifferentiated endometrial carcinoma (UDEC) who underwent various postoperative adjuvant therapies. Methods: The independent risk factors affecting CSS were studied using univariate and multivariate Cox regression analysis, and CSS in the presence of various postoperative treatments was evaluated using Kaplan-Meier method based on the cohort with pathologically confirmed UDEC from the Surveillance, Epidemiology, and End Results (SEER) database. Meanwhile, the study included 18 cases with UDEC in our center and explored their molecular characteristics and prognosis. Results: Between 2000 and 2019, a total of 443 patients were included from the SEER database. The median CSS duration was 14 months, with corresponding 3- and 5-year CSS rates of 45.9% and 44.0%, respectively. Factors such as pTNM stage, surgical resection of primary lesion, and chemoradiation independently influenced CSS. Postoperative chemotherapy alone improved CSS in patients with initial tumor spread beyond the uterus (pT3 and pT4), or lymph node (LN) invasion, or distant metastases. Additionally, postoperative radiotherapy enhanced CSS in patients who had undergone postoperative chemotherapy, those with primary tumors progressing to stage pT3, and those with LN involvement but without distant metastases. Of the 18 patients diagnosed at our center, with a median follow-up of 15.5 months, one experienced relapse and two succumbed to UDEC, who exhibited aberrant p53 expression in immunohistochemical staining. Conclusion: Postoperative chemotherapy and radiotherapy are beneficial for UDEC patients with tumors extending beyond the uterus or involving lymph nodes.

Complete Laparoscopic Type C2 Radical Surgery for Cervical Stump Cancer: No-Look and No-Touch Techniques.

BACKGROUND: Due to previous surgical history and subsequent adhesions between pelvic organs, surgery for cervical stump cancer (CSC) is technically more challenging than surgery for cervical cancer with an intact uterus.1 We aimed to illustrate the related anatomy, surgical steps and techniques of complete laparoscopic type C2 radical surgery (CLRS) for early-stage CSC. METHODS: CLRS for six patients with CSC was performed from January 2021 to January 2022. We demonstrated the detailed skills of parametrial management during CLRS for CSC in case 5 by means of a video. A 58-year-old woman diagnosed with International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IIA1 CSC received CLRS through five operative ports (Fig. 1). RESULTS: The magnetic resonance imaging (MRI) scans and gross appearance of the specimen are shown in Fig. 2. The median age and body mass index (BMI) of the six patients were 53 years and 23.8, respectively. The median blood loss was 275 mL; the median time of operation was 218 min; the median length of hospitalization was 15 days; and the median time to recover urinary function was 12 days. One patient underwent postoperative radiation for pathologically proven adenocarcinoma with deep stromal invasion,2 while the other five did not. After a median follow-up of 24 months, no patients experienced complications, recurrence, or death (Table 1). CONCLUSIONS: This study details the skills of CLRS for CSC, especially space development and the 'no-look, no-touch' tumor-free principle. It is helpful for clinicians to perform safe and standardized surgery on patients with early-stage CSC. Fig. 1 Trocar placement of complete laparoscopic type C2 radical surgery for early-stage CSC. CSC cervical stump cancer, S superior, I inferior, R right, L left, U umbilicus Fig. 2 MRI scans and gross appearance of the specimen for case 5 with CSC at FIGO 2018 stage IIA1. The tumor lesion on the cervical stump is indicated by yellow arrows. a Axial T2-weighted image; b DKI image; c ADC map; d sagittal T2-weighted image; e sagittal T1-weighted image; f gross appearance of the surgical specimen. MRI magnetic resonance imaging, CSC cervical stump cancer, FIGO International Federation of Gynecology and Obstetrics, DKI diffusional kurtosis imaging, ADC apparent diffusion coefficient Table 1 Clinicopathological characteristics, operative details, and outcomes of patients with cervical stump cancer Patient no. Age at diagnosis (years) BMI Reasons for subtotal hysterectomy FIGO 2018 stage Histology Operation Operation time (mins) Blood loss (mL) Urinary catheter (days) Hospital stay (days) Complications Depth of invasion LVSI LNs dissected TNM stage Tumor size (mm) Postoperative radiotherapy Follow-up (months) Recurrence Death 1 50 25.9 Uterine myoma IIA1 ASC CLRS+PLND 221 360 10 12 No Middle one-third N 13 T2a1N0M0 16 No 30 No No 2 55 17.3 Uterine myoma IB1 AC CLRS+PLND 191 270 20 12 No Deep one-third N 24 T1b1N0M0 10 Yes 20 No No 3 50 24.8 Uterine myoma IB1 SC CLRS+PLND 295 310 13 15 No Superficial one-third N 21 T1b1N0M0 15 No 25 No No 4 63 30.1 Uterine myoma IB1 SC CLRS+PLND 213 180 6 16 No Superficial one-third N 25 T1b1N0M0 15 No 19 No No 5 58 20.2 Postpartum hemorrhage IIA1 SC CLRS+PLND 220 100 11 14 No Middle one-third N 21 T2a1N0M0 15 No 24 No No 6 46 22.7 Uterine myoma IB1 SC CLRS+PLND 215 120 14 17 No Superficial one-third N 26 T1b1N0M0 12 No 23 No No BMI body mass index, FIGO International Federation of Gynecology and Obstetrics, ASC cervical adenosquamous carcinoma, AC cervical adenocarcinoma, SC cervical squamous carcinoma, CLRS+PLND complete laparoscopic radical surgery and pelvic node dissections, LVSI lymphovascular space invasion, N negative, LNs lymph nodes, TNM tumor node metastasis.

Identification of prognostic factors and construction of nomogram to predict cancer-specific survival for patients with ovarian granulosa cell tumors.

BACKGROUND: Ovarian granulosa cell tumors (OGCTs) feature low incidence, indolent growth and late recurrence. Treatment for recurrent OGCTs is challenging. METHODS: The present study was designed to explore the prognostic factors and establish a nomogram to predict cancer-specific survival (CSS) for OGCTs patients. Enrolled in the study were 1459 eligible patients in the Surveillance, Epidemiology, and End Results (SEER) database, who were randomized to the training (n = 1021) or testing set (n = 438) at a ratio of 7:3. Univariate and multivariate Cox regression analyses were employed to screen the prognostic factors. The predictors were determined by using the Least absolute shrinkage and selection operator (LASSO) regression analysis. The model was constructed via the Cox proportional hazards risk regression analysis. The performance and clinical value of the nomograms was assessed with C-index, calibration plots, and decision curve analysis. RESULTS: Age, pTNM stage, tumor size, surgery of the primary tumor, surgery of regional lymph nodes (LNs), residual disease after surgery, and chemotherapy were considered as significant predictive factors for CSS in OGCTs patients. After screening, the prognostic factors except surgery of regional LNs and chemotherapy were employed to build the nomogram. With desirable discrimination and calibration, the nomogram was more powerful in predicting CSS than the American Joint Committee on Cancer staging system in clinical use. CONCLUSION: This novel prognostic nomogram, which comprises a stationary nomogram and a web-based calculator, offers convenience for clinicians in personalized decision-making including optimal treatment plans and prognosis assessments for OGCTs patients.

Comparison of poly (ADP-ribose) polymerase inhibitors (PARPis) as maintenance therapy for newly-diagnosed and platinum-sensitive recurrent ovarian cancer with BRCA mutational status: a systematic review and network meta-analysis.

BACKGROUND: Poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) treatment for ovarian cancer (OC) are ever-changing. This study aimed to compare the efficacy and overall safety of available PARPi as maintenance therapy for BRCA mutation status in patients with newly diagnosed and platinum-sensitive recurrent (PSR) OC patients. RESEARCH DESIGN AND METHODS: Relevant RCTs were systematically retrieved from PubMed and Embase until 31 May 2022. Progression-free survival (PFS) and overall survival (OS) based on BRCA mutation status and adverse events (AEs) regardless of mutation were efficacy and safety endpoints. RESULTS: In newly diagnosed BRCAm-OC patients, olaparib (HR: 0.33; 95% confidence interval [CI]: 0.25, 0.43) and other PARPis [niraparib (HR: 0.40; 95% CI: 0.29, 0.55), rucaparib (HR: 0.40; 95% CI: 0.21, 0.76) and veliparib (HR: 0.44; 95% CI: 0.28, 0.69)] had a statistically significant effect on PFS versus placebo. In BRCAm-PSROC patients, Olaparib exhibited significant benefit (HR: 0.69; 95% CI: 0.54, 0.88) for OS compared to other PARPis. In BRCAwt-PSR OC patients, Olaparib showed a favorable OS benefit than other PARPis (HR: 0.84; 95% CI: 0.57,1.22). Overall, safety profile of all PARPis was acceptable. CONCLUSION: All PARPis showed significant benefit, with olaparib showing greater benefit in newly diagnosed and PSR OC women. REGISTRATION: CRD42021288932.

Metal-Organic Framework-Mediated Synergistic Hypoxia-Activated Chemo-Immunotherapy Induced by High Intensity Focused Ultrasound for Enhanced Cancer Theranostics.

High intensity focused ultrasound (HIFU) has attracted considerable attention as a noninvasive, efficient, and economic therapeutic modality for solid tumors. However, HIFU surgery has its intrinsic limitation in completely ablating tumors, leading to residual tumor tissue. Furthermore, the severely hypoxic environment ensuring after surgery can exacerbate the unrestricted proliferation and metabolism of residual tumor cells, leading to tumor recurrence and metastasis. To address these limitations, a versatile HIFU-specific metal-organic framework nanosystem (called ADMOFs) is developed by coordinating hypoxia-activated prodrug AQ4N, Mn2+ , and DOX based on the postoperative response to changes in the tumor microenvironment. ADMOFs loaded with AQ4N/Mn2+ exhibited remarkable tumor-targeting behavior in vivo and enhanced photoacoustic/magnetic resonance imaging effects, enabling more accurate guidance for HIFU surgery. After surgery, the ADMOFs exploited the severely hypoxic tumor environment induced by HIFU, overcoming hypoxia-associated drug resistance, and inducing immunogenic cell death. Finally, it effectively inhibited tumor growth and eliminated lung metastasis. Transcriptome studies revealed that this strategy significantly up-regulated genes involved in apoptosis, cell cycle, and HIF-1 signaling pathway while downregulating genes related to tumor proliferation and metastasis. These findings suggest that combining hypoxia-activated chemo-immunotherapy with HIFU is a promising strategy for enhancing cancer theranostics.

LINC01012 upregulation promotes cervical cancer proliferation and migration via downregulation of CDKN2D.

The incidence and mortality of cervical cancer (CC) rank fourth among those of all gynecological malignancies. Long noncoding RNAs (lncRNAs) serve important roles in the development of various types of cancer. The aim of the present study was to explore the role of lncRNAs in the pathogenesis of CC and to identify novel therapeutic targets. LINC01012 was identified to be associated with an unfavorable prognosis in patients with CC based on bioinformatics analyses. Upregulated LINC01012 expression was further verified in CC samples and in cervical intraepithelial neoplasia grade 3 tissues compared with healthy tissues using reverse transcription-quantitative PCR. Functionally, following transfection with LINC01012 short hairpin RNA (sh-LINC01012), the proliferation and migration of CC cell lines were examined using 5-ethynyl-2'-deoxyuridine staining, colony formation and Transwell assays, which demonstrated that knockdown of LINC01012 in CC cells suppressed cell proliferation and migration in vitro and tumor growth in an in vivo xenograft model. The potential mechanisms of LINC01012 were further explored. A negative association between LINC01012 and cyclin dependent kinase inhibitor 2D (CDKN2D) was also identified based on The Cancer Genome Atlas data and this was confirmed using western blotting and rescue experiments. Consistently, knockdown of LINC01012 in CC cells upregulated CDKN2D expression. The inhibition of proliferation and migration of CC cells following transfection with sh-LINC01012 was reversed following co-transfection of sh-LINC01012 and CDKN2D short hairpin RNA. These findings suggested that upregulated LINC01012 expression in CC may stimulate the proliferation and migration of cancer cells, thus promoting CC progression via downregulation of CDKN2D.

Banoxantrone Coordinated Metal-Organic Framework for Photoacoustic Imaging-Guided High Intensity Focused Ultrasound Therapy.

Photoacoustic (PA) imaging with high spatial resolution has great potential as desired monitoring means in the high-intensity focused ultrasound (HIFU) surgery of tumor. However, its penetration depth in the tissue is insufficient for achieving accurate intraoperative navigation, leading to residual tumor tissue. Nanomedicine provides a new opportunity for PA imaging to guide HIFU surgery. Studies have found that the hypoxic heterogeneity of tumor is effectively reversed by HIFU. Herein, a specific metal-organic framework nanosystem, constructed by coordination of banoxantrone (AQ4N) and Mn2+ , is designed based on HIFU to reverse the hypoxic heterogeneity of tumors. It can provide exogenous light-absorbing substances, thus improving the penetrability of PA imaging signal through the deep tissue and achieving clearer PA imaging for guiding HIFU surgery. In turn, AQ4N, in the hypoxic homogenous environment of the tumor provided by HIFU, is activated sequentially to specifically treat the residual hypoxic tumor cells. This combination treatment manifests higher tumor suppressors activation and lower expression of genes related to tumor progression. This strategy addresses the dissatisfaction with PA imaging-guided HIFU therapy and is promising for translation into a clinical combination regimen.

Development and validation of a novel nomogram to predict cancer-specific survival in patients with uterine cervical adenocarcinoma.

BACKGROUND: The treatment strategies and prognostic factors for uterine cervical adenocarcinoma (UAC) primarily refer to that for squamous cell carcinoma (SCC). However, the biological behavior, treatment outcomes of UAC differ from that of SCC. This study aimed to develop and validate a prognostic nomogram for predicting the probability of 3- and 5-year cancer-specific survival (CSS) in patients with UAC. METHODS: A total of 8,991 UAC patients from the Surveillance, Epidemiology, and End Results (SEER) database were included in this study. Patients diagnosed between 1988 and 2010 (n=5,655) were enrolled for model development and internal validation, and those diagnosed between 2011 and 2016 (n=3,336) were used for temporal validation. The least absolute shrinkage and selection operator (LASSO) regression analysis was used to select predictors of CSS. Cox hazard regression analysis was used to construct the model, which was presented as a static nomogram and web-based dynamic nomogram. The nomogram was internally validated using the bootstrap resampling method and underwent temporal validation. RESULTS: Tumor grade, stage T, stage N, stage M, tumor size, and surgery of the primary site were identified as independent prognostic factors for CSS and subsequently incorporated into construction of the nomogram. The nomogram could accurately predict 3- and 5-year CSS with an optimism adjusted c-statistic of 0.90 [95% confidence intervals (CI): 0.89-0.91] and 0.89 (95% CI: 0.88-0.91) after internal validation, respectively; while, after temporal validation, the statistics were 0.89 (95% CI: 0.87-0.91) and 0.88 (95% CI: 0.83-0.94), respectively. The internal and temporal calibration plots demonstrated good consistency between the predicted and observed values of CSS. Based on the model, the cases were stratified into high- and low-risk groups. The Kaplan-Meier plot showed that high-risk patients exhibited significantly poorer survival than those at low risk (P<0.0001). The prediction model exhibited a good discriminative ability and an optimal accuracy. CONCLUSIONS: In the form of a static nomogram or an online calculator, an effective and convenient nomogram was developed and validated to help clinicians quantify the risk of mortality, make personalized survival assessments, and create optimal treatment plans for UAC patients.

LINC00294 induced by GRP78 promotes cervical cancer development by promoting cell cycle transition.

Cervical cancer is one of the most common gynecological malignancies, and it has become a crucial public health problem. In the present study, the expression profiles of cervical cancer and normal cervical tissues were downloaded from the Gene Expression Omnibus and The Cancer Genome Atlas databases. Subsequently, the dysregulated long non-coding RNAs (lncRNAs) in cervical cancer were identified using R software Differentially expressed lncRNAs in cervical cancer that were associated with glucose-regulated protein 78 (GRP78) were screened out and the results demonstrated that eight lncRNAs were strongly positively correlated with GRP78. In order to confirm the relationship between GRP78 and candidate lncRNAs, GRP78 small interfering RNA (siRNA) was transfected into HeLa cells. The target lncRNAs that were regulated by GRP78 were then identified by reverse transcription-quantitative PCR and it was revealed that LINC00294 was significantly downregulated following GRP78-knockdown. Subsequently, Gene Set Enrichment Analysis demonstrated that LINC00294 was mainly enriched in regulating the cell cycle and the Hedgehog pathway. Following transfection of HeLa and SiHa cells with LINC00294 siRNA, the cell cycle was arrested at the G0/G1 phase. Western blotting suggested that LINC00294-knockdown downregulated the expression of cell cycle-associated factors (cyclin D, cyclin E and cyclin Dependent kinase 4) and upregulated cell cycle inhibitory factors (p16 and p21). The Hedgehog pathway was inhibited following knockdown of LINC00294 in HeLa and SiHa cells. In summary, LINC00294 induced by GRP78 promoted the progression of cervical cancer by regulating the cell cycle via Hedgehog pathway.

Long intergenic non-protein-coding RNA 01446 facilitates the proliferation and metastasis of gastric cancer cells through interacting with the histone lysine-specific demethylase LSD1.

Growing evidences illustrated that long non-coding RNAs (lncRNAs) exhibited widespread effects on the progression of human cancers via various mechanisms. Long intergenic non-protein-coding RNA 01446 (LINC01446), a 3484-bp ncRNA, is known to locate at chromosome 7p12.1. However, its biological functions and specific action mechanism in gastric cancer (GC) are still unclear. In our study, LINC01446 was proved to be markedly upregulated in GC tissues relative to the normal tissues, and positively correlated with the poor survival of GC patients. The multivariate Cox regression model showed that LINC01446 functioned as an independent prognostic factor for the survival of GC patients. Functionally, LINC01446 facilitated the proliferation and metastasis of GC cells. Moreover, RNA-seq analysis demonstrated that LINC01446 knockdown primarily regulated the genes relating to the growth and migration of GC. Mechanistically, LINC01446 could widely interact with histone lysine-specific demethylase LSD1 and recruit LSD1 to the Ras-related dexamethasone-induced 1 (RASD1) promoter, thereby suppressing RASD1 transcription. Overall, these findings suggest that LINC01446/LSD1/RASD1 regulatory axis may provide bona fide targets for anti-GC therapies.

Quantitative assessment of diffusion kurtosis imaging depicting deep myometrial invasion: a comparative analysis with diffusion-weighted imaging.

PURPOSE: We aimed to investigate histogram analysis of diffusion kurtosis imaging (DKI) and conventional diffusion-weighted imaging (DWI) to distinguish between deep myometrial invasion and superficial myometrial invasion in endometrial carcinoma (EC). METHODS: A total of 118 pathologically confirmed EC patients with preoperative DWI were included. The data were postprocessed with a DKI (b value of 0, 700, 1400, and 2000 s/mm2) model for quantitation of apparent diffusion values (D) and apparent kurtosis coefficient values (K) for non-Gaussian distribution. The apparent diffusion coefficient (ADC) was postprocessed with a conventional DWI model (b values of 0 and 800 s/mm2). A whole-tumor analysis approach was used. Comparisons of the histogram parameters of D, K, and ADC were carried out for the deep myometrial invasion and superficial myometrial invasion subgroups. Diagnostic performance of the imaging parameters was assessed. RESULTS: The Dmean, D10th, and D90th in deep myometrial invasion group were significantly lower than those in superficial invasion group (P < 0.001, P < 0.001, and P = 0.023, respectively), as well as the ADCmean, ADC10th, and ADC90th (P = 0.001, P = 0.001, and P = 0.042, respectively). The Kmean and K90th were significantly higher in deep invasion group than those in superficial myometrial invasion group (P = 0.002 and P = 0.026, respectively). The D10th, Kmean, and ADC10th had a relatively higher area under the curve (AUC) (0.72, 0.66, and 0.71, respectively) than other parameters for distinguishing deep myometrial invasion of EC. D10th showed a relatively higher AUC than ADC10th for the differentiation of lesions with deep myometrial invasion from those with superficial myometrial invasion (0.72 vs. 0.71), but the variation was not statistically significant (P = 0.35). CONCLUSION: Distribution of DKI and conventional DWI parameters characterized by histogram analysis may represent an indicator for deep myometrial invasion in EC. Both DKI and DWI models showed relatively equivalent effectiveness.

Upregulated lncRNA UCA1 inhibits trophoblast cell invasion and proliferation by downregulating JAK2.

Numerous studies have suggested that urothelial cancer-associated 1 (UCA1) acts as a suppressor gene affecting cell proliferation and migration. However, the biological role and the potential mechanism of UCA1 in the progression of pre-eclampsia (PE) remains unclear. The UCA1 level was markedly upregulated in PE pregnancies relative to non-PE ones in GSE75010 and tissues. A higher body mass index (BMI), maximum systolic blood pressure (BP), and maximum diastolic BP were observed in PE pregnancies, whereas the newborn weight z-score was lower compared with those of non-PE pregnancies. Knockdown of UCA1 accelerated the proliferative migratory abilities and cell cycle progression, but inhibited apoptosis of HTR-8/SVneo and JAR cells. Then, we found that Janus kinases 2 (JAK2) was negatively correlated with UCA1. In addition, JAK2 was downregulated in the placenta of PE pregnancies and was negatively regulated by UCA1. UCA1 was mainly enriched in the nucleus. Knockdown of UCA1 reduced the occupancies of the enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) and H3K27me3 on the Janus kinase 2 (JAK2) promoter regions. Finally, rescue experiments found that transfection of short-hairpin JAK2 attenuated proliferative and migratory abilities of trophoblasts, which were partially reversed after UCA1 knockdown. In short, UCA1 is upregulated in the trophocytes of PE pregnancies and accelerates trophoblast cell invasion and proliferation by downregulating JAK2.

LINC01342 promotes the progression of ovarian cancer by absorbing microRNA-30c-2-3p to upregulate HIF3A.

Ovarian cancer (OC) is a highly prevalent gynecologic malignancy and its mortality is extremely high. Therefore, the development of novel therapeutic approaches for OC is of great significance. In this study, LINC01342 was upregulated in OC tissue in the GSE38666 microarray and in tumor tissue samples collected in our center. The silencing of LINC01342 suppressed the proliferative and metastatic capacities of A2780 and HO8910 cells. Subcellular distribution assays showed that LINC01342 was mainly enriched in the cytoplasm. Subsequently, the downregulation of microRNA-30c-2-3p was proven to be the target of LINC01342. The silencing of microRNA-30c-2-3p enhanced the clonality and migratory capacity of OC cells. Moreover, the silencing of microRNA-30c-2-3p could reverse the inhibited migration and clonality in OC cells caused by LINC01342 knockdown. In addition, hypoxia-inducible factor 3 subunit α (HIF3A) was proven to be the target gene of microRNA-30c-2-3p, which was upregulated. HIF3A was negatively regulated by microRNA-30c-2-3p but positively regulated by LINC01342 in OC cells. An RNA binding protein immunoprecipitation assay showed that microRNA-30c-2-3p, LINC01342, and HIF3A could bind to argonaute RISC catalytic component 2. The overexpression of HIF3A reversed the inhibited migration and clonality in OC cells with LINC01342 knockdown. By analyzing the follow-up data from the enrolled OC patients, the LINC01342 and HIF3A levels were negatively correlated with prognosis, while the microRNA-30c-2-3p level was positively correlated with the same. In short, the upregulated LINC01342 in OC absorbs microRNA-30c-2-3p to release HIF3A. Thus, upregulated HIF3A expression accelerates the progression of OC.

Upregulated LINC00565 Accelerates Ovarian Cancer Progression By Targeting GAS6.

BACKGROUND: Long noncoding RNAs (lncRNAs) have been identified to participate in tumorigenesis. However, the underlying mechanisms of differentially expressed lncRNAs engaged in diseases remain indistinct and need further exploration. METHODS: Raw data files downloaded from TCGA and GEO dataset were used to analyze the differentially expressed lncRNAs and LINC00565 was picked out as the potential oncogene. qRT-PCR was used to analyze the LINC00565 level in ovarian tissues and cell lines. Subsequently, the selected ovarian tumor cells were then transfected with LINC00565 siRNA by Lipofectamine 2000 and the cell cycle was detected by flow cytometry. Effect of LINC00565 on tumor growth and cell cycle was verified by tumor formation assay in nude mice. The mechanism of LINC00565 involving in cell cycle regulation was further explored by Western blot. RESULTS: In this research, we discovered that LINC00565, a novel lncRNA, was highly expressed in ovarian cancer (OC). LINC00565 expression level was negatively associated with outcomes of OC patients. Further analysis showed that LINC00565 expression was closely correlated to tumor size, FIGO stage, but not related to other clinical features. In vitro experiments indicated that knockdown of LINC00565 significantly inhibited proliferative, invasive and migratory abilities of ovarian cancer cells. Besides, knockdown of LINC00565 can induce cell cycle arrest in G0/G1 phase. In addition, in vivo assay showed that low expression of LINC00565 inhibited the growth of OC. Further study found that LINC00565 knockdown markedly downregulated the protein expressions of CyclinD1, CyclinE1 and CDK4, but upregulated the expression of P16 and P21. Subsequently, we confirmed that LINC00565 promoted the progression of OC via upregulating GAS6, which has been confirmed to promote tumor progression. CONCLUSION: In summary, our study firstly reported that the LINC00565 functioned as an oncogene to promote the progression of OC by interacting with GAS6.

LINC01210 accelerates proliferation, invasion and migration in ovarian cancer through epigenetically downregulating KLF4.

BACKGROUND: In recent years, a large number of studies have shown that differentially expressed lncRNAs in tumors are capable of inducing tumorigenesis and promoting tumor development. However, the role of LINC01210 in OC still remains unclear. METHODS: Relative levels of LINC01210 and KLF4 in OC tissues containing in the GSE40595 dataset and those collected in our hospital were determined. Prognostic potential of LINC01210 in OC was evaluated by Kaplan-Meier method. Correlation between expression levels of LINC01210 and KLF4 was assessed by Spearman correlation test. After silence of LINC01210 in A2780 and HO8910 cells, changes in proliferative, migratory and invasive abilities were examined. Moreover, the interaction between LINC01210 and KLF4 was explored by RIP and ChIP. Rescue experiments were conducted to uncover the involvement of KLF4 in LINC01210-regulated OC progression. RESULTS: LINC01210 was upregulated in OC tissues and KLF4 was downregulated. LINC01210 level was higher in OC patients with metastases or advanced stage. Besides, its level was negatively correlated to DFS (disease-free survival) and OS (overall survival) of OC patients. Silence of LINC01210 attenuated proliferative, migratory and invasive abilities in A2780 and HO8910 cells. Through analyzing the GSE40595 dataset, LINC01210 was found to be negatively linked to KLF4. RIP assay further verified the interaction between LINC01210 and KLF4. Knockdown of LINC01210 markedly decreased the recruitment ability of EZH2 to KLF4. Importantly, silence of KLF4 could reverse regulatory effects of LINC01210 on cellular behaviors of OC. CONCLUSIONS: LINC01210 is upregulated in OC and predicts a poor prognosis. It accelerates proliferation, invasion and migration in OC cells through epigenetically downregulating KLF4.

Analysis of the risk factors of residual lesions after conization and prognosis of multifocal micro-invasive squamous cell cervical carcinoma treated with different types of surgery.

The aim of the present study was to evaluate the residual lesions after conization and the clinical outcome of patients with multifocal micro-invasive squamous cell cervical carcinomas (MMSCCs) treated with different surgical strategies. A retrospective study was carried out in 98 patients with MMSCCs diagnosed by conization and treated between January 2010 and December 2016 in 2 institutions. The patients underwent further different surgeries as therapeutic conization, extrafascial hysterectomy (ES), modified radical hysterectomy (MRH), radical hysterectomy (RH) with or without pelvic lymph node dissection (PLND) and regular follow-up. The clinicopathological characteristics of all of the patients were recorded. The risk factors of residual lesions and that of the recurrence were also analyzed in the present study. The logistic regression analysis revealed that cone margins (P=0.001) were correlated with residual disease after conization whereas parameters including age, gravidity, parity, menopause, stage, LVSI and the number of lesions were not predictors of residual lesions. The cone margin status also indicated the incidence of residual disease as follows: The risk of residual disease was lower with a negative margin when compared with the margin with micro-invasive carcinoma [MIC; odds ratio (OR)=0.064, P=0.012] and was lower in margin with a high-grade intraepithelial lesion than the margin with MIC (OR=0.297, P=0.287). The Cox regression analysis revealed that there were no significant correlations between the following surgery scales and postoperative recurrences, nor were any significant correlations found between the recurrences and the gravidity and parity, postmenopausal state, stage, residual disease after conization, margin status, LVSI and number of lesions (P>0.05). Positive cone margin was the only predictive factor for residual disease in patients with MMSCCs. There were no significant correlations between the surgical scales and postoperative recurrences. This result may be due to the excellent prognosis of MICs despite multiple lesions, regardless the treatment.

Glucose-Related Protein 78 Expression and Its Effects on Cisplatin-Resistance in Cervical Cancer.

BACKGROUND GRP78, the 78-kDa glucose-regulated protein, occupies a significant position in endoplasmic reticulum stress. Emerging evidences have shown that GRP78 induces chemoresistance in several tumors; however, the role of GRP78 in cervical cancer (CVC) still needs to be elucidated clearly. MATERIAL AND METHODS In the present study, we determined the expression levels of GRP78 in CVC tissues collected from patients through immuocytochemistry, western blot and real-time PCR. To evaluate the exact role of GRP78 in CVC cells in the presence of cisplatin, we generated GRP78 knock-down cervical cancer cells through small interfering RNA. After successful transfection, the apoptosis rate was assessed with flow cytometry. The expression levels of caspase-3, CHOP and Bcl-2 in GRP78 knock-down cells were determined by western blot. RESULTS The GRP78 levels in CVC tissues were increased significantly. Three types of CVC cells HeLa, SiHa, and C33A were treated with different concentrations of cisplatin and cultured for 12 hours, 24 hours, and 48 hours respectively. And SiHa cells exhibited the highest resistance to cisplatin at all time. Specifically, after 25 µM cisplatin treatment, more than 80% of C33A cells underwent apoptosis, whereas the apoptotic rate of SiHa cells was only 30-40%. Data suggested that GRP78 silencing increased chemo-sensitivity and improved the effects of cisplatin-induced apoptosis in SiHa cells. Moreover, inhibition of GRP78 could upregulate caspase-3 and CHOP expression and downregulate Bcl-2 expression. CONCLUSIONS GRP78 may represent a key bio-marker of CVC and silencing GRP78 may strengthen the resistance against cisplatin. GRP78 may be a potential molecular target for CVC therapies in future.

miR-181a Inhibits Cervical Cancer Development via Downregulating GRP78.

Cervical cancer is among the most common cancers inflicting women worldwide. Understanding the pathological mechanisms of cervical cancer development is critical for identifying novel targets for cervical cancer treatment. MicroRNAs (miRs) have various roles in regulating cancer development. In this study, we investigated the potential role of miR-181a and its target in regulating cervical cancer development and chemotherapy resistance. The expression of miR-181a was evaluated and modulated in several human cervical cancer cell lines. The role of miR-181a in regulating cervical cancer growth and chemotherapy sensitivity was investigated in cell culture models and mouse tumor xenograft models. The target of miR-181a and its function were identified in cervical cancer models. We found a distinct expression profile for miR-181a in cervical cancer cell lines. Low expression of miR-181a was closely related to cervical cancer growth and oxaliplatin resistance. HSPA5/GRP78 was identified as a target of miR-181a in cervical cancer cells. Upregulation of GRP78 led to a high cell proliferation rate and oxaliplatin resistance in cervical cancer models. In a retrospective cervical cancer cohort, high GRP78 expression was correlated with poor survival. miR-181a suppressed cervical cancer development via downregulating GRP78. High expression of GRP78 is a tumor-promoting factor in cervical cancer and is thus a potential target for novel treatment.