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Cancer spread to lymph nodes predicts poor survival but underlying mechanisms remain little understood. In this study, we show that overexpression of the long noncoding RNA LNMICC associates with lymph node metastasis of primary cervical cancer, where it serves as an independent high-risk factor in patient survival. Functional investigations demonstrated that LNMICC promoted lymph node metastasis by reprogramming fatty acid metabolism, by recruiting the nuclear factor NPM1 to the promoter of the fatty acid binding protein FABP5. We also found that the prometastatic effects of LNMICC were directly targeted and suppressed by miR-190. Our results establish a new mechanism of lymph node metastasis and highlight LNMICC as a candidate prognostic biomarker and therapeutic target in cervical cancer.Significance: These results establish the role of a novel long noncoding RNA in lymph node metastasis, with implications as a candidate prognostic biomarker and therapeutic target in cervical cancer. Cancer Res; 78(4); 877–90. ©2017 AACR.

Supplementary_Methods show the detailed experimental methods used in our paper.

Supplementary Figures show LNMICC promotes metastasis though FABP5-mediated FA metabolism in vitro, which is Suppressed by miR190.

Supplementary Tabless show LNMICC was independent prognostic factor for the OS of cervical cancer patients and a high-risk factor for pelvic LN metastasis.

Brown adipose tissue (BAT) is a highly specialized adipose tissue in its immobile location and size during the entire adulthood. In response to cold exposure and other β3-adrenoreceptor stimuli, BAT commits energy consumption by nonshivering thermogenesis (NST). However, the molecular machinery in controlling the BAT mass in adults is unknown. Here, we show our surprising findings that the BAT mass and functions can be manipulated in adult animals by controlling BAT adipocyte differentiation in vivo. Platelet-derived growth factor receptor α (PDGFα) expressed in BAT progenitor cells served a signaling function to avert adipose progenitor differentiation. Genetic and pharmacological loss-of-function of PDGFRα eliminated the differentiation barrier and permitted progenitor cell differentiation to mature and functional BAT adipocytes. Consequently, an enlarged BAT mass (megaBAT) was created by PDGFRα inhibition owing to increases of brown adipocyte numbers. Under cold exposure, a microRNA-485 (miR-485) was identified as a master suppressor of the PDGFRα signaling, and delivery of miR-485 also produced megaBAT in adult animals. Noticeably, megaBAT markedly improved global metabolism, insulin sensitivity, high-fat-diet (HFD)-induced obesity, and diabetes by enhancing NST. Together, our findings demonstrate that the adult BAT mass can be increased by blocking the previously unprecedented inhibitory signaling for BAT progenitor cell differentiation. Thus, blocking the PDGFRα for the generation of megaBAT provides an attractive strategy for treating obesity and type 2 diabetes mellitus (T2DM).

The prognosis for cervical cancer (CC) patients with lymph node metastasis (LNM) is extremely poor. Lipid droplets (LDs) have a pivotal role in promoting tumor metastasis. The crosstalk mechanism between LDs and LNM modulated in CC remains largely unknown.This study aimed to construct a miRNA-dependent progonostic model for CC patients and investigate whether miR-532-5p has a biological impact on LNM by regualting LDs accumulation.LASSO-Cox regression was applied to establish a prognostic prediction model. miR-532-5p had the lowest P-value in RNA expression (P 0.001) and prognostic prediction (P 0.0001) and was selected for further study. The functional role of the prognostic miR-532-5p-correlated competing endogenous RNA (ceRNA) network was investigated to clarify the crosstalk between LDs and LNM. The underlying mechanism was determined using site-directed mutagenesis, dual luciferase reporter assays, RNA immunoprecipitation assays, and rescue experiments. A xenograft LNM model was established to evaluate the effect of miR-532-5p and orlistat combination therapy on tumor growth and LNM.A novel 5-miRNAs prognostic signature was constructed to better predict the prognosis of CC patient. Further study demonstrated that miR-532-5p inhibited epithelial-mesenchymal transition and lymphangiogenesis by regulating LDs accumulation. Interestingly, we also found that LDs accumulation promoted cell metastasis in vitro. Mechanistically, we demonstrated a miR-532-5p-correlated ceRNA network in which LINC01410 was bound directly to miR-532-5p and effectively functioned as miR-532-5p sponge to disinhibit its target gene-fatty acid synthase (Our findings highlight a LD accumulation-dependent mechanism of miR-532-5p-modulated LNM and support treatment with miR-532-5p/orlistat as novel strategy for treating patients with LNM in CC.

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.

Background Ovarian cancer (OC) is a common gynecological malignancy correlated with a poor prognosis. Cuproptosis is a newly discovered form of cell death and has a close relationship with cancers, but the relationship between OC and cuproptosis remains unclear. Results In this study, we explored cuproptosis-related genes (CRGs) in public databases and found most CRGs are closely related to survival, and the potential roles of FDX1, LIAS and SLC31A1 in proliferation and migration were discovered in OC cell line. Afterwards, all 791 OC patients were divided into 2 clusters and the pathway enrichment and survival time showed obvious difference. 70 differentially expressed genes between 2 clusters were utilized to construct a gene signature. Significant difference was found in survival time and tumor-infiltrating immune cells among different risk groups. Finally, sensitivity of 12 commonly-used chemotherapeutic drugs was predicted closely correlating with risk score, which may provide a new strategy for clinical practice. Conclusion In conclusion, our study suggests that cuproptosis may play an important role in the progression of OC. We combinedly analyze cuproptosis-related differentially-associated genes in TCGA and GEO database and construct a risk model, which may provide new understandings to the treatment of OC.

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.

Lymph node (LN) metastasis is one of the most malignant clinical features in patients with cervical cancer (CCa). Understanding the mechanism of lymph node metastasis will provide treatment strategies for patients with CCa. Circular RNAs (circRNA) play a critical role in the development of human cancers. However, the role and mechanism of circRNAs in lymph node metastasis remain largely unknown. Here, it is reported that loss expression of circRNA circVPRBP was closely associated with LN metastasis and poor survival of CCa patients. In vitro and in vivo assays showed that circVPRBP overexpression notably inhibited lymphangiogenesis and LN metastasis, whereas RfxCas13d mediated silencing of circVPRBP promoted lymphangiogenesis and the ability of the cervical cancer cells to metastasize to the LNs. Mechanistically, circVPRBP could bind to RACK1 and shield the S122 O-GlcNAcylation site to promote RACK1 degradation, resulting in inhibition of Galectin-1 mediated lymphangiogenesis and LN metastasis in CCa. Taken together, the results demonstrate that circVPRBP is a potential prognostic biomarker and a novel therapeutic target for LN metastasis in CCa patients.

Circular RNAs (circRNAs) are a new type of regulatory RNAs, which have been identified to play critical role in various tumors. However, the profiles and roles of circRNAs in cervical cancer (CCa) have not been fully understood and need to be further explored. In the present study, we performed circRNA array and mRNA-sequencing (mRNA-Seq) to profile the differentially expressed circRNAs and mRNAs in CCa tissues. A total of 397 differentially expressed circRNAs and 2138 differentially expressed mRNAs were detected, respectively. Subsequently, a circRNA-miRNA-mRNA regulatory network was constructed and indicated that hsa_circ_0026377 was downregulated in CCa. Overexpression of hsa_circ_0026377 inhibited HeLa and SiHa cells proliferation, migration and invasion. Collectively, this study provided new insights into the circRNA profiles in CCa and suggested that hsa_circ_0026377 might play important roles in CCa development.

Lymphocyte-based immunotherapy has emerged as a breakthrough in cancer therapy for both hematologic and solid malignancies. In a subpopulation of cancer patients, this powerful therapeutic modality converts malignancy to clinically manageable disease. However, the T cell- and chimeric antigen receptor T (CAR-T) cell-mediated antimetastatic activity, especially their impacts on microscopic metastatic lesions, has not yet been investigated. Here we report a living zebrafish model that allows us to visualize the metastatic cancer cell killing effect by tumor- infiltrating lymphocytes (TILs) and CAR-T cells in vivo at the single-cell level. In a freshly isolated primary human melanoma, specific TILs effectively eliminated metastatic cancer cells in the living body. This potent metastasis-eradicating effect was validated using a human lymphoma model with CAR-T cells. Furthermore, cancer-associated fibroblasts protected metastatic cancer cells from T cell-mediated killing. Our data provide an in vivo platform to validate antimetastatic effects by human T cell-mediated immunotherapy. This unique technology may serve as a precision medicine platform for assessing anticancer effects of cellular immunotherapy in vivo before administration to human cancer patients.

FGF-2 displays multifarious functions in regulation of angiogenesis and vascular remodeling. However, effective drugs for treating FGF-2+ tumors are unavailable. Here we show that FGF-2 modulates tumor vessels by recruiting NG2+ pricytes onto tumor microvessels through a PDGFRβ-dependent mechanism. FGF-2+ tumors are intrinsically resistant to clinically available drugs targeting VEGF and PDGF. Surprisingly, dual targeting the VEGF and PDGF signaling produces a superior antitumor effect in FGF-2+ breast cancer and fibrosarcoma models. Mechanistically, inhibition of PDGFRβ ablates FGF-2-recruited perivascular coverage, exposing anti-VEGF agents to inhibit vascular sprouting. These findings show that the off-target FGF-2 is a resistant biomarker for anti-VEGF and anti-PDGF monotherapy, but a highly beneficial marker for combination therapy. Our data shed light on mechanistic interactions between various angiogenic and remodeling factors in tumor neovascularization. Optimization of antiangiogenic drugs with different principles could produce therapeutic benefits for treating their resistant off-target cancers., Anti-VEGF therapy has many limitations that might be resolved by using combination treatment approaches. Here, the authors demonstrate that the dual-targeting of VEGF and PDGF is required for targeting resistant FGF2+ tumors which depend on the recruitment of pericytes on tumor microvessels.

Endometrial cancer (EC) is one of the most common gynecological malignancies in women, accompanied by the increasing incidence and decreasing age of onset. Pyroptosis plays an important role in the occurrence and development of malignant tumors. However, the relationship between pyroptosis-related genes and tumor prognosis remains unclear. In this study, analyzing the expression levels and survival data of 33 pyroptosis-related genes in the Cancer Genome Atlas (TCGA) between normal samples and tumor samples, we obtained six pyroptosis-related prognostic differentially expressed genes (DEGs). Then, through the least absolute shrinkage and selection operator (LASSO) regression analysis, a gene signature composed of six genes (GPX4, GSDMD, GSDME, IL6, NOD2 and PYCARD) was constructed and divided patients into high- and low-risk groups. Subsequently, Kaplan-Meier (KM) plot, receiver operating characteristic (ROC) curve and principal component analysis (PCA) in two cohorts demonstrated that the gene signature was an efficient independent prognostic indicator. The enrichment analysis and immune infiltration analysis indicated that the high-risk group generally has lower immune infiltrating cells and less active immune function. In short, we constructed and validated a pyroptosis-related gene signature to predict the prognosis of EC, which is correlated to immune infiltration and proposed to help the precise diagnosis and therapy of EC.

Cervical cancer (CC) patients with lymph node metastasis (LNM) have a poor prognosis. Clarification of the detailed mechanisms underlying LNM may provide potential clinical therapeutic targets for CC patients with LNM. However, the molecular mechanism of LNM in CC is unclear. In the present study, we demonstrated that fatty acid synthase (FASN), one of the key enzymes in lipid metabolism, had upregulated expression in the CC samples and was correlated with LNM. Moreover, multivariate Cox proportional hazards analysis identified FASN as an independent prognostic factor of CC patients. Furthermore, gain-of-function and loss-of-function approaches showed that FASN promoted CC cell migration, invasion, and lymphangiogenesis. Mechanistically, on the one hand, FASN could regulate cholesterol reprogramming and then activate the lipid raft-related c-Src/AKT/FAK signaling pathway, leading to enhanced cell migration and invasion. On the other hand, FASN induced lymphangiogenesis by secreting PDGF-AA/IGFBP3. More importantly, knockdown of FASN with FASN shRNA or the inhibitors C75 and Cerulenin dramatically diminished LNM in vivo, suggesting that FASN plays an essential role in LNM of CC and the clinical application potential of FASN inhibitors. Taken together, our findings uncover a novel molecular mechanism in LNM of CC and identify FASN as a novel prognostic factor and potential therapeutic target for LNM in CC.

Recognition of specific antigens expressed in cancer cells is the initial process of cytolytic T cell‐mediated cancer killing. However, this process can be affected by other non‐cancerous cellular components in the tumor microenvironment. Here, it is shown that interleukin‐33 (IL‐33)‐activated macrophages protect melanoma cells from tumor‐infiltrating lymphocyte‐mediated killing. Mechanistically, IL‐33 markedly upregulates metalloprotease 9 (MMP‐9) expression in macrophages, which acts as a sheddase to trim NKG2D, an activating receptor expressed on the surface of natural killer (NK) cells, CD8+ T cells, subsets of CD4+ T cells, iNKT cells, and γδ T cells. Further, MMP‐9 also cleaves the MHC class I molecule, cell surface antigen‐presenting complex molecules, expressed in melanoma cells. Consequently, IL‐33‐induced macrophage MMP‐9 robustly mitigates the tumor killing‐effect by T cells. Genetic and pharmacological loss‐of‐function of MMP‐9 sheddase restore T cell‐mediated cancer killing. Together, these data provide compelling in vitro and in vivo evidence showing novel mechanisms underlying the IL‐33‐macrophage‐MMP‐9 axis‐mediated immune tolerance against cancer cells. Targeting each of these signaling components, including IL‐33 and MMP‐9 provides a new therapeutic paradigm for improving anticancer efficacy by immune therapy., T cells execute specific killing effects on cancer cells through recognition of cell surface molecules expressed in both cells. This article shows that interleukin‐33‐stimulated macrophages produce MMP‐9 that eliminates cell surface molecules in immune cells and cancer cells. Through this mechanism, MMP‐9 debilitates the T cell‐medicated anticancer effects.

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.

Background The pathogenesis and developmental mechanism of early-stage (FIGO 2009 IA2-IIA2) cervical cancer (CC) remain unclear. Seeking novel molecular biomarkers based on The Cancer Genome Atlas (TCGA) will facilitate the understanding of CC pathogenesis and help evaluate early-stage CC prognosis. Methods To identify prognosis-related genes in early-stage CC, we analyzed TCGA mRNA-seq data and clinical data by univariate Cox and Kaplan–Meier plotter analyses. Differential expression analysis identified upregulated genes in early-stage CC. Combined with the genes correlated with unfavorable prognosis, we selected desmoglein-2 (DSG2) for further investigation. To detect DSG2 expression in early-stage CC, we used immunohistochemistry (IHC), quantitative real-time PCR (qRT-PCR) and western blotting. The relationship between the expression of DSG2 and clinical features was analyzed by the Chi square test. Cox analysis was applied to assess the relationship between CC overall survival (OS) and risk factors. The correlations between DSG2 expression and CC cell line proliferation and migration were investigated with Cell Counting Kit-8 (CCK-8) and migration assays. Results There were 416 prognosis-related genes in early-stage CC. DSG2, matrix metallopeptidase 1 (MMP1), carbonic anhydrase IX (CA9), homeobox A1 (HOXA1), and serine protease inhibitor B3 (SERPINB3) were upregulated in early-stage CC compared with adjacent noncancerous tissue (ANT) and correlated with unfavorable prognosis. Among them, DSG2 was most significantly correlated with patient survival. Coexpression analysis indicated that DSG2 was probably involved in cell division, positive regulation of transferase activity, positive regulation of cell migration, EGFR upregulation pathway and regulation of lymphangiogenesis. IHC, qRT-PCR and western blotting showed that DSG2 expression was higher in CC than in normal tissue. Significant correlations were identified between DSG2 expression and several aggressive clinical features, including pelvic lymph node metastasis (PLNM). Multivariate Cox analysis showed that DSG2 and PLNM were independent prognostic factors for OS. DSG2 knockdown inhibited CC cell proliferation and migration. Conclusions DSG2 is a biomarker that promotes tumor proliferation and metastasis and is correlated with poor prognosis in early-stage CC.

Background: Cervical cancer remains a leading cause of death in women due to metastasis to distant tissues and organs. Integrins are involved in cancer metastasis. However, whether integrin α3 participates in cervical cancer metastasis is under investigation. In this study, we explored the effect and detailed mechanism through which integrin α3 regulates cervical cell migration, invasion, and angiogenesis. Methods: First, we explored the mRNA and protein expression levels of integrin α3 in cervical cancer cell lines and tissue samples obtained from patients. After knocking down the expression of integrin α3 using shRNA, the proliferation, migration, and invasion of cervical cancer cells, as well as the possible signaling pathways involved, were investigated in vitro. In addition, tube formation, proliferation, and migration of human umbilical vein endothelial cells were tested to identify their effect on angiogenesis. Zebrafish tumor migration and nude mouse lung metastasis models were utilized for the in vivo analysis. Results: We examined samples from 142 patients with cervical cancer and 20 normal cervixes. Integrin α3 was highly expressed in patients and predicted poor overall survival and disease-free survival. In SiHa cells, treatment with integrin α3 shRNA induced the phosphorylation of protein focal adhesion kinase and enhanced focal adhesion. These events were mediated by the activation of c-Src and extracellular signal-regulated protein kinase cascades. Consequently, integrin α3 increased the migratory ability of SiHa cells. In addition, knockdown of integrin α3 decreased the tube formation, proliferation, and migration of human umbilical vein endothelial cells, as well as the levels of matrix metalloproteinase-9, indicating its effect on angiogenesis. Stable transfection with integrin α3 shRNA reduced the migratory ability of SiHa cells in the zebrafish model and diminished lung metastasis in the xenograft mouse model. Conclusion: Integrin α3 recruits the c-Src/extracellular signal-regulated protein kinase cascade, leading to phosphorylation of focal adhesion kinase. Moreover, it regulates focal adhesion, endowing cervical cancer cells with potentiated migratory and invasive ability, and promotes angiogenesis via matrix metalloproteinase-9. Our findings may shed light on the mechanism involved in cervical cancer metastasis and highlight integrin α3 as a candidate prognostic biomarker and therapeutic target in patients with cervical cancer.

Additional file 1. Supplemental Figure S1–S2 : Figure S1. The bioinformatic analyses of prognosis-relative gene. a GO terms identified in the GO analysis for correlated coding genes in the cell component categories with 5 minimum P-adjusted values. GO terms identified in the GO analysis for correlated coding genes in the molecular function categories with 5 minimum P values (All P-adjusted value = 1). b Chromosome distribution of prognosis-relative gene. c Protein–protein interaction network of prognosis-relative gene. d GO terms identified in the GO biological process analysis for negatively coexpressed genes in categories with 20 minimum P-adjusted values. Oncogenic signature for negatively coexpressed genes with 20 minimum P-adjusted values. The number of enriched oncogenic signatures for negatively correlated genes was only 18. Figure S2. The effect of siRNA on CC cells detected by qRT-PCR (a) and Western blot (b). ****P < 0.0001.

A 23-year-old female patient with refractory chylous ascites was successfully treated with laparoscopic ligation of the ruptured lymphatic vessel. The young patient developed abdominal distention after right-side pelvic lymph node dissection for dysgerminoma of the right ovary. Conservative managements failed to control the symptoms. Laparoscopic surgery was performed after oral administration of peanut oil, revealing the presence of a whitish fluid in the abdominal cavity. The responsible lesion of the chylous ascites was detected in the right obturator fossa and ligated with the HEM-O-LOK System (Kangji Medical Instrument Co., Ltd., Hangzhou City, Zhejiang Province, China). The patient experienced an uneventful recovery and has been completely free of symptoms for 1 year. Laparoscopic surgery should be considered as a treatment of choice for intractable chylous ascites, and peanut oil could be used before surgery as an effective way to facilitate detection of the leakage during surgery.

Cancer Cells In article number 2101029 by Yihai Cao and co‐workers, it is shown that interleukin‐33 (IL‐33)‐activated macrophages protect melanoma cells from tumor‐infiltrating lymphocytemediated killing. This cover shows a new mechanism of immune T cell‐mediated cancer killing. In the tumor environment, macrophages produce proteases to affect the T cell and cancer cell interaction. The monkey king represents immune T cell, and the bull demon represents cancer cell. [Image: see text]

Objective: The expression level and clinical significances of long non-coding RNAs (LncRNAs) are presently unknown in the early-stage cervical cancer (CC). This study was aimed to explore the expression signatures of lncRNAs between normal and cervix carcinoma tissues and the prognostic value of LncRNAs in early-stage CC patients. Materials and Methods: The patients diagnosed with FIGO stage I-IIb CC of the First Affiliated Hospital of Sun Yat-sen University between January 1st 2006 and December 31st 2009 were retrospectively reviewed. Molecular microarray was conducted to identify differentially expression profiles of LncRNAs. In situ hybridization was applied for detection of candidate lncRNAs in cervical tissues. Results: A total of 2574 upregulated lncRNAs and 3270 downregulated lncRNAs with significantly differential expression (≥2.0-fold) were identified. Among the differentially expressed lncRNAs, RP11-396F22.1 expression was one of the most significantly overexpressed in the CC tissues compared to nomal cervical tissues (P

Cancer spread to lymph nodes predicts poor survival but underlying mechanisms remain little understood. In this study, we show that overexpression of the long noncoding RNA LNMICC associates with lymph node metastasis of primary cervical cancer, where it serves as an independent high-risk factor in patient survival. Functional investigations demonstrated that LNMICC promoted lymph node metastasis by reprogramming fatty acid metabolism, by recruiting the nuclear factor NPM1 to the promoter of the fatty acid binding protein FABP5. We also found that the prometastatic effects of LNMICC were directly targeted and suppressed by miR-190. Our results establish a new mechanism of lymph node metastasis and highlight LNMICC as a candidate prognostic biomarker and therapeutic target in cervical cancer. Significance: These results establish the role of a novel long noncoding RNA in lymph node metastasis, with implications as a candidate prognostic biomarker and therapeutic target in cervical cancer. Cancer Res; 78(4); 877–90. ©2017 AACR.

Background & Aims: The long-term oncological outcome of Class I hysterectomy to treat stage IB1 cervical cancer is unclear. The aim of the present study was to compare the surgical and long-term oncological outcomes of Class I hysterectomy and Class III radical hysterectomy for treatment of stage IB1 cervical cancer (tumor ≤ 2 cm). Methods: Seventy stage IB1 cervical cancer patients (tumor ≤ 2 cm) underwent Class I hysterectomy and 577 stage IB1 cervical cancer patients (tumor ≤ 2 cm) underwent Class III radical hysterectomy were matched with known risk factors for recurrence by greedy algorithm. Clinical, pathologic and follow-up data were retrospectively collected. Five-year survival outcomes were assessed using Kaplan-Meier model. Results: After matching, a total of 70 patient pairs (Class I - Class III) were included. The median follow-up times were 75 (range, 26-170) months in the Class III group and 75 (range, 27-168) months in the Class I group. The Class I and Class III group had similar 5-year recurrence-free survival rates (RFS) (98.6% vs. 97.1%, P = 0.56) and overall survival rates (OS) (100.0% vs. 98.5%, P = 0.32). Compared with the Class III group, the Class I group resulted in significantly shorter operating time, less intra-operative blood loss, less intraoperative complications, less postoperative complications, and shorter hospital stay. Conclusions: These findings suggest that Class I hysterectomy is an oncological safe alternative to Class III radical hysterectomy in treatment of stage IB1 cervical cancer (tumor ≤ 2 cm) and Class I hysterectomy is associated with fewer perioperative complication and earlier recovery.