The PAPSS1 gene is a modulator of response to cisplatin by regulating estrogen receptor alpha signaling activity in ovarian cancer cells.

BACKGROUND: Cancer cells may develop resistance to cisplatin by various mechanisms. Yet, the exact mechanism of cisplatin in ovarian cancer remains unclear. Recent studies have shown that 3'-phospoadenosine 5'-phosphosulfate synthase 1 (PAPSS1) inhibition combined with low-dose cisplatin increases DNA damage. The aim of this study was to determine the value of targeting PAPSS1 as a cisplatin modulator in epithelial ovarian cancer (EOC). RESULTS: Increased expression of PAPSS1 was observed in both EOC cells and tissues. Also, its higher nuclear expression was distinctly associated with FIGO (The International Federation of Gynecology and Obstetrics) stage, histological subtype, metastasis, and recurrence. Down-regulation of the PAPSS1 gene increased the cisplatin sensitivity of EOC in vitro and in vivo. Expression of PAPSS1 was negatively correlated with estrogen receptor α (ERα) in EOC. Also, low nuclear PAPSS1 and high nuclear ERα expression in EOC were associated with longer overall survival and progression-free survival in all ovarian cancer and ovarian cancer patients who received platinum-based chemotherapy. PAPSS1 silencing increased the activity of ERα-signaling in EOC cells, thus sensitizing tumors to cisplatin. CONCLUSIONS: These findings characterize a novel interplay between PAPSS1-mediated sulfation and ERα-signaling in EOC cisplatin resistance. PAPSS1 may be exploited as a cisplatin-sensitizing therapeutic target.

Targeted therapy and immunotherapy: Diamonds in the rough in the treatment of epithelial ovarian cancer.

Currently, for ovarian cancer, which has the highest mortality rate among all gynecological cancers, the standard treatment protocol is initial tumor cytoreductive surgery followed by platinum-based combination chemotherapy. Although the survival rate after standard treatment has improved, the therapeutic effect of traditional chemotherapy is very limited due to problems such as resistance to platinum-based drugs and recurrence. With the advent of the precision medicine era, molecular targeted therapy has gradually entered clinicians' view, and individualized precision therapy has been realized, surpassing the limitations of traditional therapy. The detection of genetic mutations affecting treatment, especially breast cancer susceptibility gene (BRCA) mutations and mutations of other homologous recombination repair defect (HRD) genes, can guide the targeted drug treatment of patients, effectively improve the treatment effect and achieve a better patient prognosis. This article reviews different sites and pathways of targeted therapy, including angiogenesis, cell cycle and DNA repair, and immune and metabolic pathways, and the latest research progress from preclinical and clinical trials related to ovarian cancer therapy.

Nicotinamide N-Methyltransferase: A Promising Biomarker and Target for Human Cancer Therapy.

Cancer cells typically exhibit a tightly regulated program of metabolic plasticity and epigenetic remodeling to meet the demand of uncontrolled cell proliferation. The metabolic-epigenetic axis has recently become an increasingly hot topic in carcinogenesis and offers new avenues for innovative and personalized cancer treatment strategies. Nicotinamide N-methyltransferase (NNMT) is a metabolic enzyme involved in controlling methylation potential, impacting DNA and histone epigenetic modification. NNMT overexpression has been described in various solid cancer tissues and even body fluids, including serum, urine, and saliva. Furthermore, accumulating evidence has shown that NNMT knockdown significantly decreases tumorigenesis and chemoresistance capacity. Most importantly, the natural NNMT inhibitor yuanhuadine can reverse epidermal growth factor receptor tyrosine kinase inhibitor resistance in lung cancer cells. In this review, we evaluate the possibility of NNMT as a diagnostic biomarker and molecular target for effective anticancer treatment. We also reveal the exact mechanisms of how NNMT affects epigenetics and the development of more potent and selective inhibitors.

Corrigendum: Long Non-Coding RNAs in the Tumor Immune Microenvironment: Biological Properties and Therapeutic Potential.

[This corrects the article DOI: 10.3389/fimmu.2021.697083.].

The role of CEMIP in tumors: An update based on cellular and molecular insights.

CEMIP was initially identified as an inner-ear specific protein in which three-point mutations cause folding changes in protein structure associated with non-syndromic hearing loss. CEMIP was also involved in other cellular activities, such as hyaluronan depolymerization independent of CD44 and other hyaluronidases. Growing evidence has demonstrated that CEMIP is involved in the progression of various tumors. However, whether the oncogenic effects of CEMIP relies on its enzymatic activity remain elusive. CEMIP is significantly related to metastasis and poor prognosis in patients with various tumors, suggesting that CEMIP is a potential, highly specific diagnostic tumor marker. Most preclinical experiments have shown that the overexpression of CEMIP in tumors mainly affects the adhesion, metastasis, and invasion of tumor cells and EMT. Other studies have also demonstrated that CEMIP can promote a variety of tumor processes by affecting tumor proliferation, dedifferentiation, and the tumor microenvironment. In terms of molecular mechanisms, existing research has shown that CEMIP mainly affects the WNT and EGFR signaling pathways. In addition, a variety of miRNAs have been shown to inhibit CEMIP in tumors. This paper elaborates on the clinical characteristics and regulatory dysfunction of CEMIP in different cancers. CEMIP provides a new potential target for therapy of multiple tumors, which is worthy of further study.

Long Non-Coding RNAs in the Tumor Immune Microenvironment: Biological Properties and Therapeutic Potential.

Cancer immunotherapy (CIT) is considered a revolutionary advance in the fight against cancer. The complexity of the immune microenvironment determines the success or failure of CIT. Long non-coding RNA (lncRNA) is an extremely versatile molecule that can interact with RNA, DNA, or proteins to promote or inhibit the expression of protein-coding genes. LncRNAs are expressed in many different types of immune cells and regulate both innate and adaptive immunity. Recent studies have shown that the discovery of lncRNAs provides a novel perspective for studying the regulation of the tumor immune microenvironment (TIME). Tumor cells and the associated microenvironment can change to escape recognition and elimination by the immune system. LncRNA induces the formation of an immunosuppressive microenvironment through related pathways, thereby controlling the escape of tumors from immune surveillance and promoting the development of metastasis and drug resistance. Using lncRNA as a therapeutic target provides a strategy for studying and improving the efficacy of immunotherapy.

Deubiquitinating Enzymes Orchestrate the Cancer Stem Cell-Immunosuppressive Niche Dialogue: New Perspectives and Therapeutic Potential.

Cancer stem cells (CSCs) are sparks for igniting tumor recurrence and the instigators of low response to immunotherapy and drug resistance. As one of the important components of tumor microenvironment, the tumor associated immune microenvironment (TAIM) is driving force for the heterogeneity, plasticity and evolution of CSCs. CSCs create the inhibitory TAIM (ITAIM) mainly through four stemness-related signals (SRSs), including Notch-nuclear factor-κB axis, Hedgehog, Wnt and signal transducer and activator of transcription. Ubiquitination and deubiquitination in proteins related to the specific stemness of the CSCs have a profound impact on the regulation of ITAIM. In regulating the balance between ubiquitination and deubiquitination, it is crucial for deubiquitinating enzymes (DUBs) to cleave ubiquitin chains from substrates. Ubiquitin-specific peptidases (USPs) comprise the largest family of DUBs. Growing evidence suggests that they play novel functions in contribution of ITAIM, including regulating tumor immunogenicity, activating stem cell factors, upregulating the SRSs, stabilizing anti-inflammatory receptors, and regulating anti-inflammatory cytokines. These overactive or abnormal signaling may dampen antitumor immune responses. The inhibition of USPs could play a regulatory role in SRSs and reversing ITAIM, and also have great potential in improving immune killing ability against tumor cells, including CSCs. In this review, we focus on the USPs involved in CSCs signaling pathways and regulating ITAIM, which are promising therapeutic targets in antitumor therapy.

Development and Validation of a Prognostic Signature Based on Immune Genes in Cervical Cancer.

BACKGROUND: Cervical cancer is one of the most common types of gynecological malignancies worldwide. This study aims to develop an immune signature to predict survival in cervical cancer. METHOD: The gene expression data of 296 patients with cervical cancer from The Cancer Genome Atlas database (TCGA) and immune-related genes from the Immunology Database and Analysis Portal (ImmPort) database were included in this study. The immune signature was developed based on prognostic genes. The validation dataset was downloaded from the Gene Expression Omnibus (GEO) database. RESULT: The immune signature namely immune-based prognostic score (IPRS) was developed with 229 genes. Multivariate analysis revealed that the IPRS was an independent prognostic factor for overall survival (OS) and progression-free survival (PFS) in patients with cervical cancer. Patients were stratified into high IPRS and low IPRS groups, and those in the high IPRS group were associated with better survival, which was validated in the validation set. A nomogram with IPRS and stage was constructed to predict mortality in cervical cancer. CONCLUSIONS: We developed a robust prognostic signature IPRS that could be used to predict patients' survival outcome.

Exosomes: Powerful weapon for cancer nano-immunoengineering.

Cancer immunotherapy (CIT) that targets the tumor immune microenvironment is regarded as a revolutionary advancement in the fight against cancer. The success and failure of CIT are due to the complexity of the immunosuppressive microenvironment. Cancer nanomedicine is a potential adjuvant therapeutic strategy for immune-based combination therapy. Exosomes are natural nanomaterials that play a pivotal role in mediating intercellular communications and package delivery in the tumor microenvironment. They affect the immune response or the effectiveness of immunotherapy. In particular, exosomal PD-L1 promotes cancer progression and resistance to immunotherapy. Exosomes possess high bioavailability, biological stability, targeting specificity, low toxicity, and immune characteristics, which indicate their potential for cancer therapy. They can be engineered to act as effective cancer therapeutic tools that activate anti-tumor immune response and start immune surveillance. In the current review, we introduce the role of exosomes in a tumor immune microenvironment, highlight the application of engineered exosomes to CIT, and discuss the challenges and prospects for clinical application.

Immunotherapy for Ovarian Cancer: Adjuvant, Combination, and Neoadjuvant.

Ovarian cancer is the most lethal gynecologic malignancy. Surgery and chemotherapy are the primary treatments for ovarian cancer; however, patients often succumb to recurrence with chemotherapeutic resistance within several years after the initial treatment. In the past two decades, immunotherapy has rapidly developed, and has revolutionized the treatment of various types of cancer. Despite the fact that immunotherapy response rates among ovarian cancer patients remain modest, treatment with immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR)- and TCR-engineered T cells is rapidly developing. Therapeutic efficiency could be improved significantly if immunotherapy is included as an adjuvant therapy, in combination with chemotherapy, radiation therapy, and the use of anti-angiogenesis drugs, and poly ADP ribose polymerase inhibitors (PARPi). Newly developed technologies that identify therapeutic targets, predict treatment efficacy, rapidly screen potential immunotherapy drugs, provide neoadjuvant immunotherapy, and utilize nanomedicine technology provide new opportunities for the treatment of ovarian cancer, and have the potential to prolong patient survival. However, important issues that may hinder the efficacy of such approaches, including hyperprogressive disease (HPD), immunotherapy-resistance, and toxicity of the treatments, including neurotoxicity, must be taken into account and addressed for these therapies to be effective.

E2F1/2/7/8 as independent indicators of survival in patients with cervical squamous cell carcinoma.

BACKGROUND: Cervical cancer is the second leading cause of death in women 20-39 years old. Because coverage for cervical cancer screening is low, and the vaccination rate of human papillomavirus (HPV) is poor in some countries, potential markers to detect the disease at early stages are needed. E2F transcription factors (E2Fs) are a family of transcription factors that function in cell proliferation, differentiation, apoptosis, and tumorigenesis. As abnormal activation and regulation of E2Fs are related to tumor development and poor prognosis, we performed bioinformatic analyses and in vitro assays to evaluate the role of E2Fs in cervical cancer. METHODS: Transcriptional expression of E2Fs was initially evaluated in silico using ONCOMINE and Gene Expression Profiling Interactive Analysis (GEPIA), followed by evaluation of E2F1/2/7/8 protein levels using immunohistochemistry in 88 patient tissues. E2F2 and E2F7 mRNA levels were measured by RT-qPCR. LinkedOmics and Metascape were used to predict functions of E2Fs, and in vitro experiments were performed to assess the tumorigenic role of E2F2 and E2F7. RESULTS: In silico analysis showed that E2F1/2/7/8 were significantly overexpressed in cervical cancer, findings which were confirmed at the protein level using immunohistochemistry. Further, upregulation of E2F1/2/7/8 was associated with different clinicopathological prognostic factors, including positivity for lymph vessel invasion and deep invasion of cervical stroma. Increased expression of E2F1/2/7/8 was also related to shorter overall survival (OS) and disease-free survival (DFS) in patients with cervical cancer. Using multivariate analysis, we confirmed E2F1/2/7/8 as independent prognostic factors for shorter OS of patients with cervical cancer. Finally, in vitro experiments showed that E2F2 and E2F7 are involved in cell proliferation and migration and cell cycle regulation in both HPV-positive and HPV-negative cervical cancer cells. CONCLUSIONS: E2F1/2/7/8 may be prognostic biomarkers for survival of patients with cervical cancer. E2F2 and E2F7 are involved in cell proliferation, migration, and cell cycle in both HPV-positive and HPV-negative cervical cancer cells.

Long Non-coding RNA DANCR as an Emerging Therapeutic Target in Human Cancers.

Long noncoding RNAs (lncRNAs) are emerging as important regulators of numerous biological processes, especially in cancer development. Aberrantly expressed and specifically located in tumor cells, they exert distinct functions in different cancers via regulating multiple downstream targets such as chromatins, RNAs, and proteins. Differentiation antagonizing non-protein coding RNA (DANCR) is a cytoplasmic lncRNA that generally works as a tumor promoter. Mechanically, DANCR promotes the functions of vital components in the oncogene network by sponging their corresponding microRNAs or by interacting with various regulating proteins. DANCR's distinct expression in tumor cells and collective involvement in pro-tumor pathways make it a promising therapeutic target for broad cancer treatment. Herein, we summarize the functions and molecular mechanism of DANCR in human cancers. Furthermore, we introduce the use of CRISPR/Cas9, antisense oligonucleotides and small interfering RNAs as well as viral, lipid, or exosomal vectors for onco-lncRNA targeted treatment. Conclusively, DANCR is a considerable promoter of cancers with a bright prospect in targeted therapy.

Circulating tumor cells in precision oncology: clinical applications in liquid biopsy and 3D organoid model.

Circulating tumor cells (CTCs) are a rare subset of cells found in the blood of patients with solid tumors, which function as a seed for metastases. Cancer cells metastasize through the bloodstream either as single migratory CTCs or as multicellular groupings-CTC clusters. The CTCs preserve primary tumor heterogeneity and mimic tumor properties, and may be considered as clinical biomarker, preclinical model, and therapeutic target. The potential clinical application of CTCs is being a component of liquid biopsy. CTCs are also good candidates for generating preclinical models, especially 3D organoid cultures, which could be applied in drug screening, disease modeling, genome editing, tumor immunity, and organoid biobanks. In this review, we summarize current knowledge on the value and promise of evolving CTC technologies and highlight cutting-edge research on CTCs in liquid biopsy, tumor metastasis, and organoid preclinical models. The study of CTCs offers broad pathways to develop new biomarkers for tumor patient diagnosis, prognosis, and response to therapy, as well as translational models accelerating oncologic drug development.

Curaxin CBL0137 Exerts Anticancer Activity via Diverse Mechanisms.

Chemotherapy with or without radiation remains the first choice for most cancers. However, intolerant side effects and conventional drug resistance restrict actual clinical efficacy. Curaxin CBL0137 is designed to regulate p53 and nuclear factor-κB simultaneously and to prevent the resistance caused by a single target. Functionally, CBL0137 exhibits an antitumor activity in multiple cancers, including glioblastoma, renal cell carcinoma, melanoma, neuroblastoma, and small cell lung cancer (SCLC). Mechanistically, CBL0137 is originally identified to act by facilitates chromatin transcription (FACT) complex. Further investigations reveal that several pathways, such as NOTCH1 and heat shock factor 1 (HSF1), are involved in the process. CBL0137 has been reported to target cancer stem cells (CSCs) and enhance chemotherapy/monotherapy efficacy. The translational advance of CBL0137 into clinical practice is expected to provide a promising future for cancer treatment.

Overexpression of eukaryotic initiation factor 5A2 (EIF5A2) is associated with cancer progression and poor prognosis in patients with early-stage cervical cancer.

AIMS: As one of the only two isoforms of the eukaryotic initiation factor (EIF)5A family, EIF5A2 plays an important role in tumour progression and prognosis evaluation. The aim of this study was to investigate EIF5A2 expression in International Federation of Gynecology and Obstetrics (FIGO) stage I-II cervical cancer and to evaluate its clinical significance. METHODS AND RESULTS: The mRNA and protein expression levels of EIF5A2 were analysed in 20 tissue samples of FIGO stage I-II cervical cancer and paired surrounding non-tumour cervical tissues by real-time polymerase chain reaction and western blot analysis. Immunohistochemistry was performed to examine EIF5A2 protein expression in paraffin-embedded tissues from 314 patients with cervical cancer. The mRNA and protein expression levels of EIF5A2 were significantly elevated in tumour tissues. The increased EIF5A2 expression was correlated with higher FIGO stage (P < 0.001), deep cervical stromal invasion (P = 0.026), lymphovascular space involvement (P = 0.002), pelvic lymph node metastasis (P < 0.001) and postoperative recurrence (P < 0.001) in patients with cervical cancer. Patients with tumours showing high EIF5A2 expression had a poorer survival time than those with normal EIF5A2 expression, especially the patients with negative pelvic lymph nodes and FIGO stage II. In addition, multivariate Cox analysis showed that high EIF5A2 expression was an independent prognostic factor for overall survival [hazard ratio 1.949; 95% confidence interval (CI) 1.116-3.404; P = 0.019] and disease-free survival (hazard ratio 1.980; 95% CI 1.189-3.297; P = 0.009). CONCLUSIONS: EIF5A2 overexpression may contribute to cancer progression and poor prognosis. Therefore, EIF5A2 could be a novel potential prognostic marker for FIGO stage I-II cervical cancer.

Association of insulin gene variable number of tandem repeats regulatory polymorphism with polycystic ovary syndrome.

The present meta-analysis aimed to investigate the association between insulin gene variable number of tandem repeats (INS VNTR) and polycystic ovary syndrome (PCOS). Systematic searches of electronic databases, reference lists of included articles, and the abstracts presented at related scientific societies meetings were performed. Statistical analyses were conducted using software Stata 11.0. The pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were applied. Publication bias was tested by Begg's funnel plot and Egger's regression test. A total of 9 studies including 1075 PCOS patients and 2878 controls were included in the meta-analysis. There were evidence of statistical significant association between INS VNTR and PCOS in allelic model (OR=1.25, 95% CI=1.08-1.43, P=0.002) and dominant model (OR=1.34, 95% CI=1.11-1.63, P=0.003) but not in additive model (OR=1.38, 95% CI=0.93-2.04, P=0.11) and recessive model (OR=1.26, 95% CI=0.96-1.65, P=0.09). No significant publication bias was shown by funnel plots and Egger's regression tests. In conclusion, our meta-analysis suggests that the III allele of INS VNTR is associated with increased risk of PCOS.

[Transvaginal endoscopic resection of rectal tumor: a report of 2 cases].

Two female patients with rectal tumor undergoing proctectomy via vagina, namely natural orifice transluminal endoscopic surgery (NOTES), are reported. The operations were performed on June 8 and August 10, 2010, respectively. No Trocar was used in the abdomen except for the transumbilical incision. There were no visible scars in the abdomen. Tubulovillous adenoma and moderately differentiated adenocarcinoma were diagnosed respectively through postoperative pathological examination. Both patients resumed normal work and life at the most recent follow up. Sexual life was satisfactory.