MYH9: A key protein involved in tumor progression and virus-related diseases.

The myosin heavy chain 9 (MYH9) gene encodes the heavy chain of non-muscle myosin IIA (NMIIA), which belongs to the myosin II subfamily of actin-based molecular motors. Previous studies have demonstrated that abnormal expression and mutations of MYH9 were correlated with MYH9-related diseases and tumors. Furthermore, earlier investigations identified MYH9 as a tumor suppressor. However, subsequent research revealed that MYH9 promoted tumorigenesis, progression and chemoradiotherapy resistance. Note-worthily, MYH9 has also been linked to viral infections, like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Epstein-Barr virus, and hepatitis B virus, as a receptor or co-receptor. In addition, MYH9 promotes the development of hepatocellular carcinoma by interacting with the hepatitis B virus-encoding X protein. Finally, various findings highlighted the role of MYH9 in the development of these illnesses, especially in tumors. This review summarizes the involvement of the MYH9-regulated signaling network in tumors and virus-related diseases and presents possible drug interventions on MYH9, providing insights for the use of MYH9 as a therapeutic target for tumors and virus-mediated diseases.

A preoperative nomogram predicting risk of lymph node metastasis for early-stage cervical cancer.

OBJECTIVE: This study aimed to develop a preoperative nomogram based on clinical and pathological characteristics to provide a more individualized and accurate estimation of lymph node metastasis (LNM) in patients with early-stage cervical cancer. METHODS: A total of 7,349 early-stage cervical cancer patients with pathologically confirmed between 1988 and 2015 were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. All the patients were divided into training (n = 5,500) and validation (n = 1,849) cohorts randomly. A cohort of 455 patients from multicenter was used for the external validation. We established a multivariate logistic regression model based on preoperative clinicopathological data, from which a nomogram was developed and validated. A predicted probability of LNM < 5% was defined as low risk. RESULTS: From multivariate logistic regression analysis, age at diagnosis, histologic subtype, tumor grade, tumor size and FIGO stage were identified as preoperative independent risk factors of LNM. The nomogram incorporating these factors demonstrated good discrimination and calibration (concordance index = 0.723; 95% confidence interval (CI), 0.707-0.738). In the validation cohort, the discrimination accuracy was 0.745 (95% CI, 0.720-0.770) and 0.747 (95% CI, 0.690-0.804), respectively. The nomogram was well calibrated with a high concordance probability. We also established an R-enabled Internet browser for LNM risk assessment, which tool may be convenient for physicians. CONCLUSIONS: We developed an effective preoperative nomogram based on clinical and pathological characteristics to predict LNM for early-stage cervical cancer. This model could improve clinical trial design and help physicians to decide whether to perform lymphadenectomy or not.

Tertiary lymphoid structures in gynecological cancers: prognostic role, methods for evaluating, antitumor immunity, and induction for therapy.

Tertiary lymphoid structures (TLSs), referred to as tertiary lymphoid organs and lymphoid tissue neogenesis, are aggregates of immune cells that occur in nonlymphoid tissues. In recent years, it has been found that TLSs within the tumor microenvironment have been associated with local adaptive immune immunity against cancer and favorable prognosis in several human solid tumors, including gynecological cancers. The issue of the prognosis of gynecological cancers, including endometrial, cervical, and ovarian cancer, is an enormous challenge that many clinical doctors and researchers are now facing. Concerning the predictive prognostic role of TLSs, effective evaluation, and quantification of TLSs in human tissues may be used to assist gynecologists in assessing the clinical outcome of gynecological cancer patients. This review summarizes the current knowledge of TLSs in gynecological cancers, mainly focusing on the potential mechanism of TLS neogenesis, methods for evaluating TLSs, their prognostic value, and their role in antitumor immune immunity. This review also discusses the new therapeutic methods currently being explored in gynecological cancers to induce the formation of TLSs.

Reduced 2,4-dienoyl-CoA reductase 1 is served as an unfavorable biomarker and is related to immune infiltration in cervical cancer.

BACKGROUND: Worldwide, cervical cancer (CC) remains the most prevalent malignancy of the female reproductive system, posing a threat to women's life and health, and increasing the medical and economic burden on society. Therefore, the search for tumor biomarkers for CC remains an important research direction. Immunotherapy has significantly improved patient outcomes, and genes related to tumor immune infiltration have been clinically relevant and highly reproducible biomarkers that affect the prognosis and response to treatment of CC. 2,4-dienoyl-CoA reductase 1 (DECR1) was considered to be an oncogene in a previous study, but relationship between DECR1 and immune infiltration was not mentioned. Our study aimed to reveal the clinical value of DECR1 in CC and to investigate its relationship with immune infiltration. METHODS: Human Protein Atlas was used to identify the localization of DECR1. The Ualcan database, TCGA, and IHC were used to assess the prognostic value of DECR1. GSEA was used to assess the possible signaling pathways of DECR1 in CC. The TIMER database was applied to reveal the relevance between DECR1 and immune infiltration. GEPIA was conducted to detect the co-relationship among DECR1, immune markers, and typical molecules of apoptosis. RESULTS: DECR1 was mainly distributed in the cytoplasm and overlapped with the endoplasmic reticulum. DECR1 was downregulated in CC compared to adjacent tissue. Survival analysis showed that patients with lower expression of DECR1 have a worse prognosis in CC. GSEA suggested that DECR1 was closely related to apoptosis signaling. TIMER showed that DECR1 was positively correlated with CD8+ T cell and CD4+ T cell but not with B cell in CC. CONCLUSION: DECR1 may be a potential cancer suppressor in CC and may be involved in apoptotic pathways and associated with immune infiltration.

Tertiary Lymphoid Structures Are Associated with a Favorable Prognosis in High-Grade Serous Ovarian Cancer Patients.

There was accumulating evidence indicating that tertiary lymphoid structures (TLSs) were strongly associated with improved survival and clinical outcome in several solid tumors. In this study, we intended to assess the presence of TLSs and their potential clinical significance in high-grade serous ovarian cancer (HGSOC). TCGA (The Cancer Genome Atlas) cohort included RNA-seq data of 376 HGSOC patients, of which 74 patients included available hematoxylin-eosin (H&E) sections; GEO (Gene Expression Omnibus) cohort, GSE140082, included microarray data of 212 HGSOC patients. TLSs were counted by pathological sections, and the relative abundance of TLSs was assessed by the unsupervised consensus clustering of 12-chemokine transcriptome signatures. The potential associations between TLSs and clinical prognosis, tumor microenvironment (TME), and immunotherapy response of HGSOC were further performed based on transcriptome data. In the H&E sections of HGSOC, TLSs were predominantly located in the stroma and invasive margin of the tumor. Pathological counting results suggested that the expression of 12 chemokines was significantly higher in samples abundant with TLSs than that in the lack of TLSs. Consensus clustering of both TCGA and GEO cohorts divided HGSOC patients into two clusters with different TLSs abundance: low- and high-TLSs. Based on transcriptome analysis, the high-TLS cluster was characterized by better clinical prognosis, a higher degree of immune infiltration, more biological pathways, higher tumor mutational burden score, and higher expression of immune checkpoints. In conclusion, TLSs strongly correlated with the immune-responsive microenvironment and remained a favorable prognostic factor independent of other clinical characteristics in HGSOC. The presence of TLSs was also associated with a potentially favorable response to immune checkpoint blockade (ICB) therapy in HGSOC.

NAP1L1 promotes tumor proliferation through HDGF/C-JUN signaling in ovarian cancer.

BACKGROUND: Nucleosome assembly protein 1-like 1 (NAP1L1) is highly expressed in various types of cancer and plays an important role in carcinogenesis, but its specific role in tumor development and progression remains largely unknown. In this study, we suggest the potential of NAP1L1 as a prognostic biomarker and therapeutic target for the treatment of ovarian cancer (OC). METHODS: In our study, a tissue microarray (TMA) slide containing specimens from 149 patients with OC and 11 normal ovarian tissues underwent immunohistochemistry (IHC) to analyze the correlation between NAP1L1 expression and clinicopathological features. Loss-of- function experiments were performed by transfecting siRNA and following lentiviral gene transduction into SKOV3 and OVCAR3 cells. Cell proliferation and the cell cycle were assessed by the Cell Counting Kit-8, EDU assay, flow cytometry, colony formation assay, and Western blot analysis. In addition, co-immunoprecipitation (Co-IP) and immunofluorescence assays were performed to confirm the relationship between NAP1L1 and its potential targets in SKOV3/OVCAR3 cells. RESULTS: High expression of NAP1L1 was closely related to poor clinical outcomes in OC patients. After knocking down NAP1L1 by siRNA or shRNA, both SKOV3 and OVCAR3 cells showed inhibition of cell proliferation, blocking of the G1/S phase, and increased apoptosis in vitro. Mechanism analysis indicated that NAP1L1 interacted with hepatoma-derived growth factor (HDGF) and they were co-localized in the cytoplasm. Furthermore, HDGF can interact with jun proto-oncogene (C-JUN), an oncogenic transformation factor that induces the expression of cyclin D1 (CCND1). Overexpressed HDGF in NAP1L1 knockdown OC cells not only increased the expression of C-JUN and CCND1, but it also reversed the suppressive effects of si-NAP1L1 on cell proliferation. CONCLUSIONS: Our data demonstrated that NAP1L1 could act as a prognostic biomarker in OC and can interact with HDGF to mediate the proliferation of OC, and this process of triggered proliferation may contribute to the activation of HDGF/C-JUN signaling in OC cells.

Comprehensive analysis of competitive endogenous RNAs networks reveals potential prognostic biomarkers associated with epithelial ovarian cancer.

Ovarian cancer (OC) is a major health threat to females, as it has high morbidity and mortality. Evidence has increasingly demonstrated that long non-coding RNAs (lncRNAs) regulate OC progression and they may have value as early diagnostic biomarkers, prognostic biomarkers and/or therapeutic targets. In the present study, the regulatory mechanisms and prognosis associated with cancer-specific lncRNAs and their related competing endogenous (ce)RNA network in OC were investigated. The differential expression profiles and prognostic significance of lncRNAs and mRNAs were systematically explored based on data from 359 OC cases from The Cancer Genome Atlas and 180 healthy individuals from the Genotype-Tissue Expression database. Functional enrichment analyses, RNA-RNA interactome prediction, ceRNA network analysis, correlation analysis and survival analysis were utilized to identify hub lncRNAs and biomarkers associated with OC diagnosis or prognosis. A total of 1,049 differentially expressed lncRNAs and 6,516 differentially expressed mRNAs between OC and healthy tissues were detected. An lncRNA-micro (mi)RNA-mRNA regulatory network in OC was further established, containing 91 lncRNAs, 23 miRNAs and 179 mRNAs. After survival analysis based on the expression of the RNAs in the ceRNA network, 8 lncRNAs, 4 miRNAs and 11 mRNAs that were significantly associated with OC patient survival (P<0.05) were obtained. Using least absolute shrinkage and selection operator-penalized Cox regression, an eight-lncRNA risk score model was generated, which was able to readily discriminate between OC and healthy individuals and predict the survival of patients with OC. In addition, the differential expression of several key lncRNAs and mRNAs was verified by reverse transcription-quantitative PCR and western blot analysis. The current study presents a novel lncRNA-miRNA-mRNA network, which provides insight into the potential pathogenesis of OC and allows the identification of prognostic biomarkers and treatment strategies for OC.

OLA1 is a potential prognostic molecular biomarker for endometrial cancer and promotes tumor progression.

Obg-like ATPase 1 (OLA1) is upregulated in the tumor tissues in different types of cancer. However, the function of OLA1 and its molecular mechanisms in endometrial cancer (EC) remain unknown. The present study aimed to elucidate OLA1 expression level and its biological function in endometrial cancer. The differential expression of OLA1 between EC tissues and non-cancerous tissues was analyzed using The Cancer Genome Atlas database and clinical samples. The association between clinicopathological characteristics and OLA1 expression was analyzed using bioinformatics analysis. Cell proliferation, migration and invasion were analyzed by short interfering RNA-mediated knockdown experiments, Cell Counting Kit-8, 5-Ethynyl-2'-deoxyuridine incorporation, wound healing, Transwell and Boyden assays. The potential signaling pathways associated with OLA1 in endometrial cancer were evaluated by Gene Set Enrichment Analysis. The expression levels of OLA1 in EC tissues were upregulated compared with that in non-cancerous tissues (P<0.001). Furthermore, patients with worse survival were found to have higher OLA1 expression, and increased OLA1 expression in endometrial cancer associated with clinical stage (P<0.01), histological type (P<0.01), histological grade (P<0.01), menstrual status (P<0.01), cancer status (P<0.05) and distant metastasis (P<0.05). In RL95-2 and HEC-1B cell lines, decreased levels of OLA1 inhibited proliferation, invasion and migration, and the TGF-ß signaling pathway, ubiquitin-mediated proteolysis and Wnt signaling pathway may be involved in these mechanisms. The present study revealed that OLA1 could be a potential prognostic indicator and therapeutic target in endometrial cancer, and that the TGF-ß signaling, Wnt signaling and ubiquitin-mediated proteolysis pathways may be regulated by OLA1.

Exosomal-lncRNA DLEU1 Accelerates the Proliferation, Migration, and Invasion of Endometrial Carcinoma Cells by Regulating microRNA-E2F3.

PURPOSE: Long non-coding RNAs (lncRNAs) may act as oncogenes in several cancers, including endometrial carcinoma (EC). The purpose of the current study is to investigate the regulatory mechanism of exosomal-lncRNA deleted in lymphocytic leukemia1 (DLEU1) on EC. METHODS: The expression levels of lncRNA DLEU1, microRNA-381-3p and E2F Transcription Factor 3 (E2F3) in EC tissues or cells were detected using quantitative reverse transcription-polymerase chain reaction (qRT-PCR). We then analysed the proliferation, migration, and invasion of EC cells by performing the MTT assay, wound healing assay, and transwell invasion assay, respectively. Identification of exosomes was detected using Western blot assay. The uptake of exosomes was detected by a confocal microscope. The effects of exosomes on EC cells were investigated by construction of cell co-culture system. The interactions among DLEU1, miR-381-3p and E2F3 were confirmed using the dual-luciferase reporter (DLR) assay. RESULTS: LncRNA DLEU1 expression was highly up-regulated in EC tissues and cells. Knockdown of DLEU1 inhibited the proliferation, migration, and invasion of EC cells. Exosomes could be uptaken by the ambient EC cells. MiR-381-3p was a target of DLEU1 and was negatively modulated by DLEU1. Overexpression of miR-381-3p suppressed the proliferation, migration, and invasion of EC cells. Additionally, E2F3 was the target gene of miR-381-3p and was negatively modulated by miR-381-3p. Upregulation of miR-381-3p and down-regulation of E2F3 reversed the promoting effect of exosomal DLEU1 on EC cells. CONCLUSION: Exosomal DLEU1 accelerates the development of EC by regulating the miR-381-3p/E2F3 axis, thus DLEU1 may act as a possible therapeutic target for treating EC.

MicroRNA-155 Suppresses the Translation of p38 and Impairs the Functioning of Dendritic Cells in Endometrial Cancer Mice.

BACKGROUND: Dendritic cells (DCs) are reported to play an important role in activating the anti-tumor immune responses. p38 MAPK14 signaling plays an important role in controlling their activity. Here, we identified that miR-155 suppressed the translation of p38 and impaired the functioning of dendritic cells in endometrial cancer. METHODS: HEC1A endometrial cancer cell lines were used for the study which was transfected in the C57BL/6 mice. Murine bone marrow-derived dendritic cells (BMDCs) were isolated from the mice. Target prediction was done by TargetScan which was confirmed by RT-PCR analysis. The protein expression was carried by Western blot analysis. Levels of IL-12 were evaluated by ELISA. Mice injected with HEC1A cells were subjected to tumor challenge study. RESULTS: On screening the binding sites of p38 MAPK14 gene, miR-155 was found to bind the 3'UTR directly and blocked its translation. The levels of miR-155 were upregulated in dendritic cells and RAW264.7 cells, miR-155 showed inhibitory effect on expression levels of p38. In dendritic cells, miR-155 was found to regulate the expression of IL-12, also miR-155 inhibitor stimulated the differentiation of Th1 cells in mice induced with endometrial cancer. In dendritic cells, miR-155 inhibited the expression of p38 gene and decreased their ability to interfere in tumor growth. CONCLUSION: The study concludes suppressive role of miR-155 in the process of dendritic cells mediated anti-tumor immunity, also inhibiting miR-155 provides a novel strategy for countering endometrial cancer.

ZEB1 promotes invasion and metastasis of endometrial cancer by interacting with HDGF and inducing its transcription.

Zinc finger E-box binding homeobox 1 (ZEB1), as a typical transcription inhibitory factor of E-cadherin, plays a major role in stimulating the invasion and metastasis of tumors via modulating the epithelial-mesenchymal transition (EMT) signal. However, its function and modulatory mechanisms in endometrial carcinoma (EC) remain unclear. In this study, silencing ZEB1 significantly reduced EC cell migration, invasion, and metastasis, as well as enhanced the sensitivity of EC cells to cisplatin (cDDP) in vitro and in vivo. Mechanism analysis indicated that ZEB1 interacts with hepatoma-derived growth factor (HDGF) and co-localizes in the nucleus. In addition, ZEB1 as a transcription factor binds to the promoter of HDGF to stimulate HDGF transcription. Furthermore, suppression of HDGF in ZEB1-overexpressed EC cells not only reduced the expression of ß-catenin, TCF4, and ZEB1, but also repressed ß-catenin translocation from the cytoplasm into the nucleus and further downregulated the combination with TCF4. Interestingly, the ß-catenin/TCF4 signaling feedback stimulates ZEB1 transcription and therefore constitutes a positive feedback loop. In clinical samples, ZEB1 positively correlates with HDGF expression, and co-expression of ZEB1 and HDGF promotes the pathogenesis of EC. In summary, our study demonstrated that the positive feedback loop of ZEB1/HDGF/ß-catenin/TCF4 plays an unfavorable role in the metastasis of endometrial carcinoma.

Low expression of KIF7 indicates poor prognosis in epithelial ovarian cancer.

The aim of the present study was to investigate kinesin family member 7 (KIF7) expression in epithelial ovarian cancer tissues (paraffin-embedded tissues and fresh) and to explore its expression, association with clinicopathological parameters and prognostic value in patients with epithelial ovarian cancer. A total of 113 paraffin-embedded tumor tissues of epithelial ovarian cancer patients diagnosed and operated at the memorial hospital of Sun Yat-sen University Between December 2009 and March 2017 and 41 paratumor tissues were collected for the present study and were assessed for KIF7 expression using immunohistochemistry. Furthermore, 22 fresh epithelial ovarian cancer tissues and their matched paratumor tissues were collected from the Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, between August 2013 and March 2019 and subjected to reverse-transcription quantitative PCR analysis to detect the mRNA expression of KIF7. The expression of KIF7 was lower in cancer tissues than in paratumor tissues, and KIF7 expression was associated with recurrence-free survival and overall survival in epithelial ovarian cancer patients. Furthermore, multivariate logistic regression analysis indicated that low KIF7 expression was an independent predictor of poor survival in patients with epithelial ovarian cancer. In conclusion, KIF7 has a tumor suppressor role in epithelial ovarian cancer and is a useful independent prognostic predictor. It may hold important value for the clinical diagnosis and treatment of epithelial ovarian cancer.

Sp1 contributes to radioresistance of cervical cancer through targeting G2/M cell cycle checkpoint CDK1.

BACKGROUND/AIMS: Radioresistance remains a significant obstacle in the therapy of cervical cancer, and the mechanism of it is still unclear. We aimed to investigate the role of specificity protein 1 (Sp1) in radioresistance of cervical cancer. METHODS: Sp1 was examined immunohistochemically on tissues from 36 human cervical cancer patients. We used RT-qPCR and Western blot to examine the expression of Sp1 in irradiated cervical cancer cell lines SiHa and HeLa. The role of Sp1 in radioresistance of cervical cancer cells was assessed by colony-formation assay and cell cycle analysis. Dual-luciferase reporter assay was performed to detect the downstream of Sp1. RESULTS: High Sp1 expression was positively correlated with advanced International Federation of Gynecology and Obstetrics (FIGO) stage, lymph node metastasis, and lymphovascular space invasion (LVSI) of cervical cancer. The expression of Sp1 was dose-dependently increased in irradiated cervical cancer cell lines at both mRNA and protein levels. Colony-formation assay showed that alteration of Sp1 expression affected the survival of cervical cancer cells with radiotherapy (RT) treatment. Knockdown of Sp1 significantly strengthened the cellular response to radiation by inducing G2/M arrest in cervical cancer cells. Overexpression of Sp1 significantly decreased G2/M arrest in cervical cancer cells, which was related to upregulation of CDK1 expression. Dual-luciferase reporter assay showed the direct effect of Sp1 on the transcriptional activation of CDK1. CONCLUSION: Sp1 may contribute to radioresistance through inhibiting G2/M phase arrest by targeting CDK1, and be considered as a potential therapeutic target to promote the effect of RT for patients with cervical cancer.

Hepatoma-Derived Growth Factor and DDX5 Promote Carcinogenesis and Progression of Endometrial Cancer by Activating ß-Catenin.

Background: Our previous work determined the correlation between high nuclear expression of hepatoma-derived growth factor (HDGF) and clinicopathological data of endometrial cancer (EC); however, the modulatory mechanisms and biological role of HDGF in EC have not been reported. Methods: Lentiviral particles carrying human HDGF short hairpin RNA (shHDGF-1, -2, and -3) vector and plasmids for HDGF, DDX5, and ß-catenin expression were, respectively introduced into EC cells to evaluate the effects and molecular mechanisms underlying EC cell proliferation, migration, invasion, and metastasis. Quantitative real time reverse transcription polymerase chain reaction (qRT-PCR) and western blotting were used to determine HDGF and DDX5 expression. Co-immunoprecipitation (co-IP), mass spectrometry, and an immunofluorescence co-localization study were conducted to explore the relationship between HDGF, DDX5, and ß-catenin. Immunohistochemistry was used to analyze the clinical associations between HDGF and DDX5 in EC. Results: Knocking down HDGF expression significantly decreased EC cellular proliferation, migration, invasion in vitro, as well as tumorigenesis and metastasis in vivo. Conversely, HDGF overexpression reversed these effects. Stable knockdown-based HDGF suppression activated the PI3K/AKT signaling pathway, along with downstream ß-catenin-mediated cell cycle and epithelial-mesenchymal transition signaling. Furthermore, co-IP combined with mass spectrometry and an immunofluorescence co-localization study indicated that HDGF interacts with DDX5, whereas ß-catenin was associated with DDX5 but not HDGF. Overexpression of DDX5 reversed the suppression of shHDGF. Immunohistochemistry analysis showed that high expression of DDX5 constituted an unfavorable factor with respect to the clinicopathological characteristics of EC tissues and that HDGF and DDX5 high expression (HDGF+/DDX5+) led to a worse prognosis for patients with EC (P < 0.001). In addition, we found that the expression of HDGF and DDX5 was positively correlated in EC tissues (r = 0.475, P < 0.001). Conclusion: Our results provide novel evidence that HDGF interacts with DDX5 and promotes the progression of EC through the induction of ß-catenin.

Mir20a/106a-WTX axis regulates RhoGDIa/CDC42 signaling and colon cancer progression.

Wilms tumor gene on the X chromosome (WTX) is a putative tumor suppressor gene in Wilms tumor, but its expression and functions in other tumors are unclear. Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in women and the second leading cause in men in the United States. We demonstrated that WTX frequently lost in CRC which was highly correlated with cell proliferation, tumor invasion and metastasis. Mechanistically, WTX loss disrupts the interaction between RhoGDIα and CDC42 by losing of the binding with RhoGDIα and triggers the activation of CDC42 and its downstream cascades, which promotes CRC development and liver metastasis. The aberrant upregulation of miR-20a/miR-106a were identified as the reason of WTX loss in CRC both in vivo and in vitro. These study defined the mechanism how miR-20a/miR-106a-mediated WTX loss regulates CRC progression and metastasis, and provided a potential therapeutic target for preventing CRC progression.

[Expression of phosphoglycerate kinase 1 in endometrial carcinoma and its association with patients' outcome].

OBJECTIVE: To investigate the expression of phosphoglycerate kinase 1 (PGK1) and its prognostic value in endometrial carcinoma (EC). METHODS: The expression of PGK1 was detected immunohistochemically in 30 normal endometrium and 130 EC specimens. The relationship between PGK1 protein expression and the clinicopathological features of the patients was evaluated. RESULTS: Immunohistochemical analysis revealed low PGK1 expression in 55.4% (72/130) and high PGK1 expression in 44.6% (58/130) of the EC specimens, as compared with the rates of 90% (27/30) and 10% (3/30) in normal endometrium, respectively (P<0.001). PGK1 expression was significantly correlated with FIGO stage (P<0.001), histological grade (P=0.002) and lymph node metastasis (P<0.001). Kaplan-Meier survival analysis indicated that patients with a high PGK1 expression had a shorter overall survival rate than those with a low PGK1 expression (P<0.001). Multivariate analysis showed that a high PGK1 expression was not the independent predictor of the prognosis of EC (P=0.077). CONCLUSION: A high expression of PGK1 is associated with aggressive and metastatic behaviors of EC, and detection of PGK1 provides assistance in evaluating the prognosis of patients with EC.

PGK1 and GRP78 overexpression correlates with clinical significance and poor prognosis in Chinese endometrial cancer patients.

The aim of this study was to measure the expression patterns of PGK1 and GRP78 in normal endometrial tissues and endometrial carcinoma, and associations between their combined effects and the pathological features of endometrial carcinoma. We used 30 normal endometrial tissue samples and 130 endometrial carcinoma samples, and separately evaluated PGK1 and GRP78 protein expression by immunohistochemistry. Scores ranging from 0 to 9 were obtained by multiplying the percentage of positive cells by the staining intensity (0-3). Immunohistochemical analysis revealed increased PGK1 and GRP78 expression in the cytoplasm of endometrial carcinoma cells compared with that in normal endometrial tissues. High PGK1 expression positively correlated with the FIGO stage (P < 0.001), histological grade (P = 0.002), and lymph node status (P < 0.001). High GRP78 expression positively correlated with the pathological type (P = 0.0125), FIGO stage (P < 0.001), and lymph node status (P < 0.001). In addition, PGK1 overexpression was positively correlated with GRP78 overexpression in endometrial carcinoma patients (P < 0.001), and the concurrent expression of both oncogenes in endometrial carcinoma patients correlated significantly with the lymph node status (P < 0.001) and FIGO stage (P < 0.001). Patients with high PGK1 and GRP78 expression levels had poorer overall survival rates than those with low expression levels of both proteins (P < 0.001). Our results suggested that the co-occurrence of PGK1 and GRP78 expression is potentially an unfavorable factor for endometrial carcinoma progression.

TGF-ß1-induced CK17 enhances cancer stem cell-like properties rather than EMT in promoting cervical cancer metastasis via the ERK1/2-MZF1 signaling pathway.

Tumor metastasis remains a major obstacle for improving overall cancer survival in cervical cancer (CC), which may be due to the existence of tumor microenvironment-related cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT). The mechanism underlying these processes needs to be further elucidated. Here, we report that TGF-ß1, one of the key microenvironmental stimuli, can enhance CSC characteristics, facilitate the EMT, and induce CK17. Silencing CK17 expression attenuated CSC-like properties without affecting the EMT markers induced by TGF-ß1, whereas forced overexpression of CK17 promoted lymphatic metastasis in vivo even without EMT inducement. Inhibitors of ERK1/2 signaling drastically decreased the induction of CK17 mediated by TGF-ß1. By combined computational and experimental approaches, we identified and validated that MZF1 was a key transcription factor binding to the promoter of CK17. Taken together, these results demonstrate that CK17 induced by the TGF-ß1-ERK1/2-MZF1 signaling pathway facilitates metastasis by promoting the acquisition of CSC properties rather than by inducing the EMT process in CC, suggesting that this CK17-related signaling pathway might be a suitable target for the development of therapy for CC metastasis.

[Role of specificity protein 1 in modulating radiosensitivity of cervical cancer cell lines].

OBJECTIVE: To investigate the role of specificity protein 1 (Sp1) in regulating radiosensitivity of cervical cancer cell lines. METHODS: We analyzed Sp1 expression in 6 different cervical cancer cell lines (SiHa, HeLa, Caski, Me180, Ms751, and C33a) using Western blotting and real-time PCR. Clonogenic survival assay and curve fitting were used to assess the changes in radiosensitivity of Me180 cells transfected with lentivirus-mediated shRNA vector targeting sp1 and HeLa cells transfected with sp1 over-expression vector. RESULTS: In the 6 cell lines tested, the cellular expression levels of Sp1 decreased gradually in the order of Me180, Caski, C33a, SiHa, Ms751, and HeLa. SP1 knockdown with lentivirus-mediated shRNA significantly lowered the survival rate of Me180 cells following radiation exposure (P<0.05), and obviously lowered the values of SF2, D0 and Dq but significantly increased α/ß of the cells. Compared with the cells transfected with the mock vector, HeLa cells with sp1 over-expression showed a significantly increased survival following radiation exposure (P<0.05) with obviously increased values of SF2, D0 and Dq but significantly lowered α/ß. CONCLUSION: Silencing Sp1 can increase the radiosensitivity while Sp1 overexpression enhances the radioresistance of cervical cancer cell lines, suggesting an important role of Sp1 in radiotherapy for cervical cancer.