Downregulation of LNMAS orchestrates partial EMT and immune escape from macrophage phagocytosis to promote lymph node metastasis of cervical cancer.

Epithelial-mesenchymal transition (EMT) is an essential step to drive the metastatic cascade to lymph nodes (LNs) in cervical cancer cells. However, few of them metastasize successfully partially due to increased susceptibility to immunosurveillance conferred by EMT. The precise mechanisms of cancer cells orchestrate EMT and immune evasion remain largely unexplored. In this study, we identified a lncRNA termed lymph node metastasis associated suppressor (LNMAS), which was downregulated in LN-positive cervical cancer patients and correlated with LN metastasis and prognosis. Functionally, LNMAS suppressed cervical cancer cells metastasis in vitro and in vivo. Mechanistically, LNMAS exerts its metastasis suppressive activity by competitively interacting with HMGB1 and abrogating the chromatin accessibility of TWIST1 and STC1, inhibiting TWIST1-mediated partial EMT and STC1-dependent immune escape from macrophage phagocytosis. We further demonstrated that the CpG sites in the promoter region of LNMAS was hypermethylated and contributed to the downregulation of LNMAS. Taken together, our results reveal the essential role of LNMAS in the LN metastasis of cervical cancer and provide mechanistic insights into the regulation of LNMAS in EMT and immune evasion.

Circular RNA hsa_circ_0043280 inhibits cervical cancer tumor growth and metastasis via miR-203a-3p/PAQR3 axis.

Circular RNAs (circRNAs) are known to act as key regulators in a variety of malignancies. However, the role of circRNAs in cervical cancer (CCa) remains largely unknown. Herein, we demonstrated that a circRNA derived from the TADA2A gene (hsa_circ_0043280) was significantly downregulated in CCa and that this reduction in expression was correlated with a poor prognosis. Furthermore, our results demonstrated that hsa_circ_0043280 functions as a tumor suppressor to inhibit tumor growth and metastasis in CCa. Mechanistically, hsa_circ_0043280 competitively sponges miR-203a-3p and prevents miR-203a-3p from reducing the levels of PAQR3. Collectively, our results demonstrate that hsa_circ_0043280 plays a pivotal role in the development and metastasis of CCa, thus suggesting that hsa_circ_0043280 has significant potential as a prognostic biomarker and a therapeutic target for CCa.

TAB2 Promotes the Stemness and Biological Functions of Cervical Squamous Cell Carcinoma Cells.

Cancer stem cells are a key population participating in the promotion of the cervical cancer progression through interacting with cancer cells. Existing studies have preliminary revealed that cervical cancer stem cells contribute to tumor recurrence and chemotherapy resistance. However, the specific mechanisms involved in regulating cell functions remain largely unknown. Here, we analyzed published data from public databases and our global transcriptome data, thus identifying cancer-related signaling pathways and molecules. According to our findings, upregulated TAB2 was correlated to stem cell-like properties of cervical cancer. Immunohistochemistry staining of TAB2 in normal and cervical cancer tissues was performed. The cell function experiments demonstrated that knockdown of TAB2 reduced the stemness of cervical cancer cells and, importantly, prevented cervical cancer progression. Collectively, the therapeutic scheme targeting TAB2 may provide an option for overcoming tumor relapse and chemoresistance of cervical cancer via obstructing stemness maintenance.

Family with sequence similarity 83 member A promotes tumor cell proliferation and metastasis and predicts poor prognosis in cervical cancer.

Family with sequence similarity 83 member A (FAM83A) is a member of the FAM83 family and is proven to have oncogenic properties in several cancers. However, the mechanisms of FAM83A in human cervical cancer (CC) progression are unknown. Here, we found that FAM83A is highly expressed in CC tissues and cell lines through western blot and qRT-PCR. We utilized GEO datasets to assess FAM83A expression in CC in comparison to the normal cervical tissue (NCT) (GSE6791), and similarly, in lymph node positive CC compared to the lymph node negative CC (GSE26511). Immunohistochemistry (IHC) was used to quantify FAM83A expression in 20 NCT and 105 CC patient samples. FAM83A expression is upregulated in early-stage CC and correlates with aggressive clinicopathologic features. Moreover, both our hospital's and TCGA datasets revealed that patients of early-stage CC with higher FAM83A expression had a poorer prognosis. Subsequently, CCK-8 and transwell assays verified that FAM83A promotes proliferation, migration, and invasion of CC cells. Additionally, Gene Set Enrichment Analysis (GSEA) revealed that FAM83A is not only involved in cell development, differentiation, and proliferation but is also correlated with cell junction assembly and cell matrix adhesion. It might also be affiliated with the regulation of tumor necrosis factor-mediated signaling pathway and the regulation of the ErbB signaling pathway in CC. These results indicate that FAM83A promotes tumor cell proliferation, migration, and metastasis. Our study provides novel evidence FAM83A may act as a promising therapeutic target for CC.

Development and validation of a survival nomogram for patients with Siewert type II/III adenocarcinoma of the esophagogastric junction based on real-world data.

BACKGROUND: The clinical staging systems for adenocarcinoma of the esophagogastric junction (AEG) are controversial. We aimed to propose a prognostic nomogram based on real-world data for predicting survival of Siewert type II/III AEG patients after surgery. METHODS: A total of 396 patients with Siewert type II/III AEG diagnosed and treated at the Center for Gastrointestinal Surgery, the First Affiliated Hospital, Sun Yat-sen University, from June 2009 to June 2017 were enrolled. The original data of 29 variables were exported from the electronic medical records system. The nomogram was established based on multivariate Cox regression coefficients, and its performance was measured using Harrell's concordance index (C-index), receiver operating characteristic (ROC) curve analysis and calibration curve. RESULTS: A nomogram was constructed based on nine variables. The C-index for overall survival (OS) prediction was 0.76 (95% CI, 0.72 to 0.80) in the training cohort, in the validation-1 cohort was 0.79 (95% CI, 0.72 to 0.86), and 0.73 (95% CI, 0.67 to 0.80) in the validation-2 cohort. Time-dependent ROC curves and calibration curves in all three cohorts showed good prognostic predictive accuracy. We further proved the superiority of the nomogram in predictive accuracy for OS to pathological TNM (pTNM) staging system and other independent prognostic factors. Kaplan-Meier survival curves demonstrated the pTNM stage, grade of differentiation, positive lymph node, log odds of positive lymph node and organ invasion were prognostic factors with good discriminative ability. CONCLUSION: The established nomogram demonstrated a more precise prognostic prediction for patients with Siewert type II/III AEG.

Identification of Long Noncoding RNA Expression Profiles in HPV-Negative Cervical Cancer.

AIM: HPV-negative cervical cancer (CC) usually appears more aggressive and causes poorer survival outcomes compared to HPV-positive cases. However, the research in regard to HPV-negative CC is rare, and the related molecular mechanism underlying remains unclear. We intended to explore the expression profiles of long noncoding RNAs (lncRNAs) and identify the tumor-associated lncRNAs which might be used as the potential biomarker for HPV-negative CC. METHODS: Bioinformatics analyses were utilized to construct the expression profiles of lncRNAs, Gene Ontology, and KEGG analyses and draw the lncRNA-mRNA co-expression network in HPV-negative CC. The expression levels of the top 5 marked-up tumor-associated lncRNAs were detected by qRT-PCR. The effect of LINC00115 on CC growth and metastasis was studied by Cell Counting Kit-8 and transwell assays. RESULTS: In comparison to normal cervix (NC), 2,052 lncRNAs were differentially expressed in HPV-negative CC. It demonstrated that LINC00115 was significantly upregulated in HPV-negative CC cells compared to NC, and it could promote proliferation, migration, and invasion of HPV-negative CC cells. CONCLUSION: LINC00115 might be a potential biomarker for HPV-negative CC.

BTB domain-containing 7 predicts low recurrence and suppresses tumor progression by deactivating Notch1 signaling in breast cancer.

PURPOSE: BTB domain-containing 7 (BTBD7) has been found to regulate epithelial tissue remodeling and branched organ formation and has been reported to modulate the biological behavior of several cancers. However, its role in breast cancer has not been identified. This study investigated the biological role and prognostic value of BTBD7 in breast cancer. METHODS: We identified the BTBD7 expression pattern using the GENT2 database and assessed its expression in breast cancer tissue and cell lines using quantitative reverse transcription polymerase chain reaction, western blot, and immunohistochemistry. We conducted a clinical relevance and survival analysis on a cohort of 121 breast cancer cases from our follow-up and validated it in a Kaplan-Meier plotter. The gain-loss effect of BTBD7 on cell proliferation, invasion, and migration was detected in vitro. We employed a xenograft mouse metastatic model for in vivo validation and performed a Cignal Finder Cancer 10-Pathway Reporter Array, western blot, immunofluorescence, Cell Counting Kit-8, and transwell invasion/migration assays to analyze the potential mechanism. RESULTS: BTBD7 was downregulated in human breast cancer cell lines and tissues. Decreased BTBD7 expression correlated with a positive lymph node status, lymphovascular invasion, and TNM stage, while high BTBD7 expression correlated with low breast cancer recurrence. BTBD7 suppressed cell proliferation, invasion/migration, and tumor metastasis in breast cancer. The mechanism studied suggested that the inhibitory role of BTBD7 was through the deactivation of Notch1 signaling in breast cancer. CONCLUSION: BTBD7 suppresses tumor progression, and its high expression correlates with low recurrence in breast cancer.

High expression of PTPRM predicts poor prognosis and promotes tumor growth and lymph node metastasis in cervical cancer.

The prognosis for cervical cancer (CCa) patients with lymph node metastasis (LNM) is dismal. Elucidation of the molecular mechanisms underlying LNM may provide clinical therapeutic strategies for CCa patients with LNM. However, the precise mechanism of LNM in CCa remains unclear. Herein, we demonstrated that protein tyrosine phosphatase receptor type M (PTPRM), identified from TCGA dataset, was markedly upregulated in CCa with LNM and correlated with LNM. Moreover, PTPRM was an independent prognostic factor of CCa patients in multivariate Cox's proportional hazards model analysis and associated with poor prognosis. Furthermore, through gain-of-function and loss-of-function approaches, we found that PTPRM promoted CCa cells proliferation, migration, invasion, lymphangiogenesis, and LNM. Mechanistically, PTPRM promoted epithelial-mesenchymal transition (EMT) via Src-AKT signaling pathway and induced lymphangiogenesis in a VEGF-C dependent manner, resulting in LNM of CCa. Importantly, knockdown of PTPRM dramatically reduced LNM in vivo, suggesting that PTPRM plays an important role in the LNM of CCa. Taken together, our findings uncover a novel molecular mechanism in the LNM of CCa and identify PTPRM as a novel prognostic factor and potential therapeutic target for LNM in CCa.

FABP5 promotes lymph node metastasis in cervical cancer by reprogramming fatty acid metabolism.

Patients with cervical cancer (CCa) with lymph node metastasis (LNM) have an extremely poor prognosis. Elucidation of the molecular mechanisms underlying LNM may provide clinical therapeutic strategies for CCa. Upregulation of fatty acid-binding protein 5 (FABP5) expression in CCa tumours was demonstrated to positively correlate with LNM. However, the precise role and mechanisms of FABP5 in the LNM of CCa remain unknown. Methods: The diagnostic value of FABP5 as a predictor of LNM in CCa was evaluated in CCa tumour samples. The functional role of FABP5 and its upstream and downstream regulatory factors were investigated by gain-of-function and loss-of-function assays in vitro and in vivo. A mouse model of LNM was used to determine the effect of FABP5 on LNM and the therapeutic value of FABP5 targeting. Results: We demonstrated that FABP5 was markedly upregulated in CCa with LNM and correlated with poor prognosis. FABP5 protein was an independent predictor of LNM in a multivariate logistic analysis. Furthermore, FABP5 promoted epithelial-mesenchymal transition, lymphangiogenesis, and LNM by reprogramming fatty acid (FA) metabolism. Mechanistically, FABP5 promoted lipolysis and FA synthesis, which led to an increase in intracellular fatty acids (FAs) that activated NF-κB signalling, thus inducing LNM. Importantly, administration of orlistat, which attenuates FA metabolism reprogramming, inhibited FABP5-induced LNM in CCa. The pro-metastatic effect of FABP5 was reduced by miR-144-3p. Moreover, miR-144-3p was significantly downregulated and FABP5 was upregulated in CCa in a hypoxic microenvironment. Conclusion: Our findings highlight a FA metabolism-dependent mechanism of FABP5-induced LNM. Moreover, the expression and biological function of FABP5 can be regulated by miR-144-3p in hypoxia. Our study identifies FABP5 as a potential diagnostic biomarker and therapeutic target for LNM in CCa.

Effect of flexible patterns of health education on enhancing the compliance of pregnant women from Tibet, China.

Prenatal examination is a pivotal measure to prevent high-risk pregnancy and to ensure the safety of both mother and infant. However, pregnant women in Linzhi Prefecture in the Tibet Autonomous Region (TAR) often cannot obtain regular prenatal examinations due to limited accessibility of healthcare facilities, shortage of medical staff, and lack of medical equipment. Health education is an important approach to solve this ever-growing issue of pregnant women in rural Tibet.To evaluate the efficacy of flexible methods of health education programs on improving compliance among pregnant women from Tibet, China.In May to November of 2018, a total of 168 pregnant women receiving prenatal examination in a tertiary referral hospital in Linzhi Prefecture were recruited and randomly assigned to a control (n = 85) and intervention group (n = 83). All pregnant women were followed up until delivery. The pregnant women in the control group received regular prenatal examination and health education programs. Other than receiving routine prenatal care, participants of the interventional group also voluntarily joined the WeChat Social Messaging platform. Online resources posted by the maternity schools provided convenience and flexibility for the pregnant woman. The number of prenatal examinations was statistically significant between the 2 groups. The effect of flexible patterns of health education programs on improving the compliance of pregnant women in Tibet was assessed.The number of prenatal examinations in the intervention group was 2.646 times, which was higher than that in the control group (P < .01). Multivariate analysis demonstrated that interventional measures and ethnicity were the influencing factors of the number of prenatal examinations for pregnant women in Linzhi after the adjustment of age, history of adverse pregnancy, education level, ethnicity, multiparity, gestational complications, and medical history. The number of prenatal examinations for the pregnant Tibetan women was 0.535 times lower compared with that of the pregnant Han women (95% CI: -0.089, 1.157, P = .091).Flexible forms of health education during the antenatal period can effectively increase the compliance of pregnant women in Tibet.