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Given that the corneal epithelium is situated on the outermost part of the eye, its functions can be influenced by external temperatures and chemical substances. This study aimed to elucidate the expression profile of chemosensory receptors in corneal epithelial cells and analyze their role in eye function regulation. A comprehensive analysis of 425 chemosensory receptors in human corneal epithelial cells-transformed (HCE-T) revealed the functional expression of TRPV4. The activation of TRPV4 in HCE-T cells significantly increased the expression of membrane-associated mucins MUC1, MUC4, and MUC16, which are crucial for stabilizing tear films, with efficacy comparable to the active components of dry eye medications. The present study suggests that TRPV4, which is activated by body temperature, regulates mucin expression and proposes it as a novel target for dry eye treatment., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yuko Terada reports financial support was provided by Japan Society for the Promotion of Science. Keisuke Ito reports financial support was provided by Japan Society for the Promotion of Science. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To investigate the association between liver enzymes and ovarian cancer (OC), and to validate their potential as biomarkers and their mechanisms in OC. Methods Genome-wide association studies for OC and levels of enzymes such as Alkaline phosphatase (ALP), Aspartate aminotransferase (AST), Alanine aminotransferase, and gamma-glutamyltransferase were analyzed. Univariate and multivariate Mendelian randomization (MR), complemented by the Steiger test, identified enzymes with a potential causal relationship to OC. Single-cell transcriptomics from the GSE130000 dataset pinpointed pivotal cellular clusters, enabling further examination of enzyme-encoding gene expression. Transcription factors (TFs) governing these genes were predicted to construct TF-mRNA networks. Additionally, liver enzyme levels were retrospectively analyzed in healthy individuals and OC patients, alongside the evaluation of correlations with cancer antigen 125 (CA125) and Human Epididymis Protein 4 (HE4)., Results: A total of 283 single nucleotide polymorphisms (SNPs) and 209 SNPs related to ALP and AST, respectively. Using the inverse-variance weighted method, univariate MR (UVMR) analysis revealed that ALP (P = 0.050, OR = 0.938) and AST (P = 0.017, OR = 0.906) were inversely associated with OC risk, suggesting their roles as protective factors. Multivariate MR (MVMR) confirmed the causal effect of ALP (P = 0.005, OR = 0.938) on OC without reverse causality. Key cellular clusters including T cells, ovarian cells, endothelial cells, macrophages, cancer-associated fibroblasts (CAFs), and epithelial cells were identified, with epithelial cells showing high expression of genes encoding AST and ALP. Notably, TFs such as TCE4 were implicated in the regulation of GOT2 and ALPL genes. OC patient samples exhibited decreased ALP levels in both blood and tumor tissues, with a negative correlation between ALP and CA125 levels observed., Conclusion: This study has established a causal link between AST and ALP with OC, identifying them as protective factors. The increased expression of the genes encoding these enzymes in epithelial cells provides a theoretical basis for developing novel disease markers and targeted therapies for OC., (© 2024. The Author(s).)

Background: The treatment for colon adenocarcinoma (COAD) faces challenges in terms of immunotherapy effectiveness due to multiple factors. Because of the high tumor specificity and immunogenicity, neoantigen has been considered a pivotal target for cancer immunotherapy. Therefore, this study aims to identify and predict the potential tumor antigens of MUC somatic mutations (MUCmut) in COAD., Methods: Three databases of TCGA, TIMER2.0, and cBioPortal were used for a detailed evaluation of the association between MUCmut and multi-factors like tumor mutation burden (TMB), microsatellite instability (MSI), prognosis, and the tumor microenvironment within the context of total 2242 COAD patients. Next, TSNAdb and the differential agretopicity index (DAI) were utilized to predict high-confidence neopeptides for MUCmut based on 531 COAD patients' genomic information. DAI was calculated by subtraction of its predicted HLA binding affinity of the MUCmut peptide from the corresponding wild-type peptide., Results: The top six mutation frequencies (14 to 2.9%) were from MUC16, MUC17, MUC5B, MUC2, MUC4 and MUC6. COAD patients with MUC16 and MUC4 mutations had longer DFS and PFS. However, patients with MUC13 and MUC20 mutations had shorter OS. Patients with the mutation of MUC16, MUC5B, MUC2, MUC4, and MUC6 exhibited higher TMB and MSI. Moreover, these mutations from the MUC family were associated with the infiltration of diverse lymphocyte cells and the expression of immune checkpoint genes. Through TSNAdb 1.0/NetMHCpan v2.8, 452 single nucleotide variants (SNVs) of MUCmut peptides were identified. Moreover, through TSNAdb2.0/NetMHCpan v4.0, 57 SNVs, 1 Q-frame shift (TS), and 157 short insertions/deletions (INDELs) of MUCmut were identified. Finally, 10 high-confidence neopeptides of MUCmut were predicted by DAI., Conclusions: Together, our findings establish the immunogenicity and therapeutic potential of mutant MUC family-derived neoantigens. Through combining the tools of TSNAdb and DAI, a group of novel MUCmut neoantigens were identified as potential targets for immunotherapy., (© 2024. The Author(s).)

The biomarker CA125, a peptide epitope located in several tandem repeats of the mucin MUC16, is the gold standard for monitoring regression and recurrence of high-grade serous ovarian cancer in response to therapy. However, the CA125 epitope along with several structural features of the MUC16 molecule are ill defined. One central aspect still unresolved is the number of tandem repeats in MUC16 and how many of these repeats contain the CA125 epitope. Studies from the early 2000s assembled short DNA reads to estimate that MUC16 contained 63 repeats.Here, we conduct Nanopore long-read sequencing of MUC16 transcripts from three primary ovarian tumors and established cell lines (OVCAR3, OVCAR5, and Kuramochi) for a more exhaustive and accurate estimation and sequencing of the MUC16 tandem repeats.The consensus sequence derived from these six sources was confirmed by proteomics validation and agrees with recent additions to the NCBI database. We propose a model of MUC16 containing 19-not 63-tandem repeats. In addition, we predict the structure of the tandem repeat domain using the deep learning algorithm, AlphaFold.The predicted structure displays an SEA domain and unstructured linker region rich in proline, serine, and threonine residues in all 19 tandem repeats. These studies now pave the way for a detailed characterization of the CA125 epitope. Sequencing and modeling of the MUC16 tandem repeats along with their glycoproteomic characterization, currently underway in our laboratories, will help identify novel epitopes in the MUC16 molecule that improve on the sensitivity and clinical utility of the current CA125 assay., Significance: Despite its crucial role in clinical management of ovarian cancer, the exact molecular sequence and structure of the biomarker, CA125, are not defined. Here, we combine long-read sequencing, mass spectrometry, and in silico modeling to provide the foundational dataset for a more complete characterization of the CA125 epitope., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Background: MUC16 is a heavily glycosylated cell surface mucin cleaved in the tumor microenvironment to shed CA125. CA125 is a serum biomarker expressed by > 95% of non-mucinous advanced stage epithelial ovarian cancers. MUC16/CA125 contributes to the evasion of anti-tumor immunity, peritoneal spread and promotes carcinogenesis; consequently, it has been targeted with antibody-based passive and active immunotherapy. However, vaccination against this self-antigen likely requires breaking B cell tolerance and may trigger autoimmune disease. Display of self-antigens on virus-like particles (VLPs), including those produced with human papillomavirus (HPV) L1, can efficiently break B cell tolerance., Results: A 20 aa juxta-membrane peptide of the murine MUC16 (mMUC16) or human MUC16 (hMUC16) ectodomain was displayed either via genetic insertion into an immunodominant loop of HPV16 L1-VLPs between residues 136/137, or by chemical coupling using malemide to cysteine sulfhydryl groups on their surface. Female mice were vaccinated intramuscularly three times with either DNA expressing L1-MUC16 fusions via electroporation, or with alum-formulated VLP chemically-coupled to MUC16 peptides. Both regimens were well tolerated, and elicited MUC16-specific serum IgG, although titers were higher in mice vaccinated with MUC16-coupled VLP on alum as compared to L1-MUC16 DNA vaccination. Antibody responses to mMUC16-targeted vaccination cross-reacted with hMUC16 peptide, and vice versa; both were reactive with the surface of CA125+ OVCAR3 cells, but not SKOV3 that lack detectable CA125 expression. Interestingly, vaccination of mice with mMUC16 peptide mixed with VLP and alum elicited mMUC16-specific IgG, implying VLPs provide robust T help and that coupling may not be required to break tolerance to this epitope., Conclusion: Vaccination with VLP displaying the 20 aa juxta-membrane MUC16 ectodomain, which includes the membrane proximal cleavage site, is likely to be well tolerated and induce IgG targeting ovarian cancer cells, even after CA125 is shed., (© 2024. The Author(s).)

Research Objective: To explore the diagnostic value of circ-DENN domain containing 4 C (circDENND4C) in epithelial ovarian cancer (EOC) and the corresponding mechanism., Methods: We determined the expression of circDENND4C and miR-200b/c in tissues and serum specimens as well as EOC cell lines using qRT-PCR. Basic clinical data, and serum HE4 and CAl25 levels were acquired from patients' clinical records. Expression-related correlations and the diagnostic value of serum circDENND4C in EOC were also estimated. CCK-8 and flow cytometry were performed to detect the effect of circDENND4C on cell proliferation and apoptosis., Results: circDENND4C level was lowest while miR-200b/c was highest in EOC tissues, followed by benign and normal tissues. Similarly, serum circDENND4C was lowest while miR-200b/c was highest in EOC patients. Moreover, serum circDENND4C was lower in patients with benign ovarian tumors than in healthy women, while miR-200b/c expression was higher. circDENND4C was negatively associated with miR-200b/c in EOC tissues and serum specimens, and serum circDENND4C was also negatively correlated with serum HE4 and CAl25 in EOC patients. circDENND4C expression in both tissue and serum was negatively related to FIGO and TNM stage, and tumor size in EOC. Serum circDENND4C could distinguish healthy persons from patients with benign ovarian tumors and EOC, and they showed a higher specificity and accuracy than serum CA125 or HE4 in EOC diagnosis. circDENND4C upregulation significantly suppressed EOC cell proliferation and facilitated apoptosis by downregulating miR-200b/c in vitro ., Conclusions: Summarily, circDENND4C acts as a tumor inhibitor by downregulating miR-200b/c in EOC and could be a possible tumor marker for EOC diagnosis.KEY MESSAGEScircDENND4C expression was lowest while miR-200b/c was highest in EOC tissues or serums, followed by benign and normal tissues or serums.circDENND4C was involved in malignant progression of EOC, concretely, overexpression of circDENND4C suppressed EOC cell proliferation and stimulated apoptosis via downregulating miR-200b/c, and circDENND4C expression in both tissue and serum was closely related to FIGO and TNM stages and tumor size in EOC.Serum circDENND4C showed a higher specificity and accuracy than serum CA125 or HE4 in EOC diagnosis.HIGHLIGHTScircDENND4C expression was lowest while miR-200b/c was highest in EOC tissues, followed by benign and normal tissues.Serum circDENND4C was lowest while miR-200b/c was highest in EOC patients, followed by benign patients and healthy women.Overexpression of circDENND4C suppresses EOC cell proliferation and stimulates apoptosis via downregulating miR-200b/c.circDENND4C expression in both tissue and serum was closely related to FIGO and TNM stage and tumor size in EOC.Serum circDENND4C showed a higher specificity and accuracy than serum CA125 or HE4 in EOC diagnosis.

Purpose: Ocular surface discomfort and dry eye disease are caused by a dysfunctional tear film. The efficacy of lubricating eye drops on the human eye is known, but the compositions may show differential effects on rescuing the tear film. Mucins form a critical layer of the tear film, a reduction of which may be causative for ocular surface conditions. Therefore, it is essential to develop relevant human-derived models to test mucin production., Methods: Human corneoscleral rims were obtained from a healthy donor (n = 8) post-corneal keratoplasty and cultured in DMEM/F12 media. Hyperosmolar stress mimicking dry eye disease was induced by exposing the corneoscleral rim tissues to +200 mOsml NaCl-containing media. The corneoscleral rims were treated with polyethylene glycol-propylene glycol (PEG-PG)-based topical formulation. Gene expression analysis was performed for NFAT5, MUC5AC, and MUC16. Secreted mucins were measured by enzyme-linked immunosorbent assay (ELISA) (Elabscience, Houston, TX, USA) for MUC5AC and MUC16., Results: The corneoscleral rims responded to hyperosmolar stress by upregulating NFAT5, a marker for increased osmolarity, as observed in the case of dry eye disease. The expression of MUC5AC and MUC16 was reduced upon an increase in hyperosmotic stress. The corneoscleral rim tissues showed induction of MUC5AC and MUC16 expression upon treatment with PEG-PG topical formulation but did not show significant changes in the presence of hyperosmolar treatments., Conclusion: Our findings showed that PEG-PG-based topical formulation slightly alleviated hyperosmolar stress-induced decrease in MUC5AC and MUC16 gene expression that is encountered in DED., Competing Interests: None

Background: Triple-negative breast cancer (TNBC) is highly aggressive with an increased metastatic incidence compared to other breast cancer subtypes. However, due to the absence of clinically reliable biomarkers and targeted therapy in TNBC, outcomes are suboptimal. Hence, there is an urgent need to understand biological mechanisms that lead to identifying novel therapeutic targets for managing metastatic TNBC., Methods: The clinical significance of MUC16 and ELAVL1 or Hu antigen R (HuR) was examined using breast cancer TCGA data. Microarray was performed on MUC16 knockdown and scramble TNBC cells and MUC16-associated genes were identified using RNA immunoprecipitation and metastatic cDNA array. Metastatic properties of MUC16 were evaluated using tail vein experiment. MUC16 and HuR downstream pathways were confirmed by ectopic overexpression of MUC16-carboxyl-terminal (MUC16-Cter), HuR and cMyc as well as HuR inhibitors (MS-444 and CMLD-2) in TNBC cells., Results: MUC16 was highly expressed in TNBC and correlated with its target HuR. Depletion of MUC16 showed decreased invasion, migration, and colony formation abilities of human and mouse TNBC cells. Mice injected with MUC16 depleted cells were less likely to develop lung metastasis (P = 0.001). Notably, MUC16 and HuR were highly expressed in the lung tropic TNBC cells and lung metastases. Mechanistically, we identified cMyc as a HuR target in TNBC using RNA immunoprecipitation and metastatic cDNA array. Furthermore, MUC16 knockdown and pharmacological inhibition of HuR (MS-444 and CMLD-2) in TNBC cells showed a reduction in cMyc expression. MUC16-Cter or HuR overexpression models indicated MUC16/HuR/cMyc axis in TNBC cell migration., Conclusions: Our study identified MUC16 as a TNBC lung metastasis promoter that acts through HuR/cMyc axis. This study will form the basis of future studies to evaluate the targeting of both MUC16 and HuR in TNBC patients., (© 2023. The Author(s).)

Cancer antigen 125 (CA125) is one of the mucin family proteins and is a serum tumor marker for various tumors, such as ovarian cancer, endometrial cancer, pancreatic cancer, and bladder cancer. CA125 is used to distinguish between benign and malignant tumors, monitor the response to chemotherapy, and detect relapse after initial treatment. Recently, CA125 was reported to be involved in chemoresistance through the physical characteristics of mucin or by modifying the immune tumor-microenvironment. However, the relationship between CA125 expression and chemoresistance in bladder cancer is still unclear. In this study, the clinicopathologic features of bladder cancer with CA125 expression and the status of the tumor-microenvironment related to gemcitabine/cisplatin resistance were investigated using publicly available data sets (Cancer Genome Atlas Expression, GSE169455 data set) from the cBioPortal website, the National Center for Biotechnology Information website, and an in-house case collection of bladder cancer. The cases with CA125 expression had poorer disease-free and overall survival rates than those without CA125 expression. A mucinous area surrounding cancer cells was frequently detected in cases with CA125 expression (81%; 13/16 cases). CA125 expression was also related to the immunosuppressive tumor-microenvironment through the infiltration of immunosuppressive immune cells, such as regulatory T cells and M2 macrophages. These results suggest that the status of tumor-microenvironment associated with CA125 is involved in gemcitabine/cisplatin resistance in bladder cancer., (Copyright © 2023 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

MUC16 is a member of the attached mucin family that encodes cancer antigen 125 (CA-125), but the association of MUC16 status with grade and subtypes of glioma patients has not yet been established. Data for MUC16 mRNA expression in 37 different cancer types were considered, and genomic data from the Cancer Genome Atlas (TCGA) from 1051 low-grade glioma (LGG) patients and 833 glioblastoma (GBM) patients were analyzed. LGG and GBM has low expression of MUC16, but it is frequently mutated in GBM. Kaplan-Meier survival analysis, glioma subtypes, methylation, and isocitrate dehydrogenase (IDH1) status were all performed. We found that mutated-MUC16 in LGG patients is associated with better prognosis considering overall survival (OS), IDH1, methylation, 1p/19q, and 10q status. Conversely, MUC16 mutation were related with worse prognosis in GBM patients upon analyzing those same parameters. Therefore, MUC16 mutations may assist in glioma diagnosis and prognosis and should be further studied in this tumor type., Competing Interests: Declaration of Competing Interest The author declares no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The prognosis of gastric cancer (GC) is difficult to predict due to the disease's complex genetic and phenotypic characteristics. MUC16 has been reported to be involved in the progression of several tumors. In this study, we aimed to explore whether MUC16 mutation had any impact on the prognosis or treatments of GC patients. Additionally, this analysis uncovered possible critical pathways related with these systems. On the cBioPortal, we were able to locate the pertinent data of patients with MUC16 mutations. And then, GSEA analysis identified differences in mRNA levels between mutant and wild-type MUC16 patients in terms of biological function annotation and pathways. The KEGG and GO analyses were also performed using the differentially expressed genes (DEGs). There were 139 individuals with GC who had the MUC16 mutation, which accounts for 32 percent, and the remaining patients had the MUC16 wild type. Survival assays revealed that patients with the MUC16 mutation had longer overall survival and disease-free survival. GSEA analysis revealed that cell cycle, cysteine and methionine metabolism, Huntington's disease, one carbon pool by folate, pyrimidine metabolism, pyruvate metabolism, RNA degradation, spliceosome, and valine leucine and isoleucine degradation were distinctly enriched in patients with MUC16 mutation type. Moreover, we identified 323 DEGs. Among them, 162 genes were upregulated, and 161 genes were downregulated. GO and KEGG assays indicated DEGs as enriched in pancreatic secretion, neuroactive ligand-receptor interaction, protein digestion and absorption, fat digestion and absorption, and glycerolipid metabolism. Overall, our data revealed that the MUC16 mutation in GC may affect the development of patients by altering several genes and pathways, indicating the importance of MUC16 mutation in the treatments of GC on an individual basis., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2022 Liang Huang et al.)

Background: Mucin 16 (MUC16), a cell surface-associated mucin, has been implicated to be upregulated in a large repertoire of malignances. However, its function in the pathogenesis of colorectal cancer (CRC) is unknown., Aims: Here, we explored the regulatory role of MUC16 in CRC., Methods: First, tumor and paracancerous tissues, and serum samples from 162 CRC patients, peripheral blood samples from 48 healthy volunteers and 72 benign colorectal patients were collected. The correlation between the MUC16 expression and the clinical phenotypes of the patients was analyzed. Subsequently, HCT116 and SW480 cells with deletion of MUC16 were established to detect changes in the growth and metastatic capacities of CRC cells. The genes with the highest correlation with MUC16 were predicted by bioinformatics, and their binding relationships were detected by Co-IP and double-labeled immunofluorescence, followed by functional rescue experiments., Results: Overexpression of MUC16 in CRC patients was positively correlated with serum biomarkers and poor prognosis of patients. It was demonstrated by in vitro and in vivo experiments that knocking-down the expression of MUC16 could significantly inhibit the growth and metastasis of CRC cells. MUC16 activated janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) by interacting with JAK2. Further overexpression of JAK2 in cells with poor expression of MUC16 revealed a significant increase in the proliferative and metastatic capacities of CRC cells., Conclusions: MUC16 contributes to the development and progression of CRC by binding to JAK2, thereby promoting phosphorylation of JAK2 and further activating STAT3 phosphorylation., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Significant strides have been made in the development of precision therapeutics for cancer. Aberrantly expressed glycoproteins represent a potential avenue for therapeutic development. The MUC16/CA125 glycoprotein serves as a biomarker of disease and a driver of malignant transformation in epithelial ovarian cancer. Previously, we demonstrated a proof-of-principle approach to selectively targeting MUC16+ cells. In this report, we performed a synthetic lethal kinase screen using a human kinome RNAi library and identified key pathways preferentially targetable in MUC16+ cells using isogenic dual-fluorescence ovarian cancer cell lines. Using a separate approach, we performed high-content small-molecule screening of six different libraries of 356,982 compounds for MUC16/CA125-selective agents and identified lead candidates that showed preferential cytotoxicity in MUC16+ cells. Compounds with differential activity were selected and tested in various other ovarian cell lines or isogenic pairs to identify lead compounds for structure-activity relationship (SAR) selection. Lead siRNA and small-molecule inhibitor candidates preferentially inhibited invasion of MUC16+ cells in vitro and in vivo, and we show that this is due to decreased activation of MAPK, and non-receptor tyrosine kinases. Taken together, we present a comprehensive screening approach to the development of a novel class of MUC16-selective targeted therapeutics and identify candidates suitable for further clinical development., (©2022 American Association for Cancer Research.)

Malignant ascites is a common clinical problem in ovarian cancer. NK cells are present in the ascites, but their antitumor activity is inhibited. The underlying mechanisms of the inhibition have yet to be fully elucidated. Using an Fcγ receptor-mediated NK cell activation assay, we show that ascites from ovarian cancer patients potently inhibits NK cell activation. Part of the inhibitory activity is mediated by CA125, a mucin 16 fragment shed from ovarian cancer tumors. Moreover, transcriptional analyses by RNA sequencing reveal upregulation of genes involved in multiple metabolic pathways but downregulation of genes involved in cytotoxicity and signaling pathways in NK cells purified from ovarian cancer patient ascites. Transcription of genes involved in cytotoxicity pathways are also downregulated in NK cells from healthy donors after in vitro treatment with ascites or with a CA125-enriched protein fraction. These results show that ascites and CA125 inhibit antitumor activity of NK cells at transcriptional levels by suppressing expression of genes involved in NK cell activation and cytotoxicity. Our findings shed light on the molecular mechanisms by which ascites inhibits the activity of NK cells and suggest possible approaches to reactivate NK cells for ovarian cancer immunotherapy., (Copyright © 2022 by The American Association of Immunologists, Inc.)

Background: Ovarian cancer (OC) is one of the serious threats to the health of women worldwide, and accurate biomarkers are urgently demanded for early diagnosis of OC. We have previously confirmed that miR-205 promotes the invasion and metastasis of OC cells by inhibiting the expression of the tumor suppressor gene TCF21. In this study, we used liquid biopsy technology to detect the expression levels of the four genes, miR-205, CA125, HE4 and TCF21, in the exosomes of plasma of OC patients. Combined with analysis of clinicopathological parameters of OC patients, we aimed to provide efficient and non-invasive laboratory biomarkers for early diagnosis of OC., Methods: 36 OC patients who were diagnosed in local hospitals from September 2020 to July 2021 were selected as OC group, 31 cases of surgically diagnosed with ovarian benign lesions were selected as benign group, and 32 healthy people who underwent physical examination during the same period were selected as a control group. We employed transmission electron microscope (TEM), Western blotting (WB), and nanoparticle tracking analysis (NTA) to identify biomarkers in the exosomes extracted from plasma of the three groups. The RNA levels of miR-205, CA125, HE4 and TCF21 genes in plasma exosomes were detected by real-time quantitative PCR (qRT-PCR) method. We used clinical pathological parameters and the Receiver Operating Characteristic (ROC) curves to evaluate the diagnostic efficacy for the genes detected in plasma exosomes., Results: We found that the expression level of miR-205 in plasma exosomes of the OC group was significantly higher than that of the benign and control groups (P <  0.05), and the level of miR-205 was elevated during the III-IV periods of OC and lymph node metastasis., Conclusion: The level of miR-205 in plasma exosomes is a valuable tumor biomarker to improve OC diagnosis., (© 2022. The Author(s).)

Background: It has been shown that low-density lipoprotein receptor-related protein 1B ( LRP1B ) mutations correlate with tumor mutation burden (TMB) and prognosis in patients with melanoma and non-small-cell lung cancer, while the relationship between LRP1B mutations and TMB in gastric cancer needs further study. This study is aimed at exploring the relationship between LRP1B mutations and TMB in gastric cancer., Methods: Mutation frequency profiles of the genes in patients with gastric cancer in TCGA-STAD dataset were analyzed by bioinformatics analysis. The relationship among LRP1B mutations, TMB, and patient clinical features in gastric cancer was investigated by the chi-square test. The TMB prediction capacity based on LRP1B mutation status was evaluated by ROC curves., Results: LRP1B is one of the top 10 genes with high gene mutation frequency in gastric cancer. The mutation status of LRP1B in gastric cancer patients was significantly correlated with age and TP53 and MUC16 mutation status. The result of ROC curve analysis revealed that the mutation status of LRP1B could be considered as an indicator of the degree of TMB in patients with gastric cancer., Conclusion: This study presented the relationship between TMB and LRP1B mutations in gastric cancer, providing a novel perspective for gastric cancer prognosis and therapy., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Sizhe Hu et al.)

An early and accurate pregnancy diagnosis method is required to improve the reproductive performance of cows. Here we developed an easy pregnancy detection method using vaginal mucosal membrane (VMM) with application of Reverse Transcription-Loop-mediated Isothermal Amplification (RT-LAMP) and machine learning. Cows underwent artificial insemination (AI) on day 0, followed by VMM-collection on day 17-18, and pregnancy diagnosis by ultrasonography on day 30. By RNA sequencing of VMM samples, three candidate genes for pregnancy markers (ISG15 and IFIT1: up-regulated, MUC16: down-regulated) were selected. Using these genes, we performed RT-LAMP and calculated the rise-up time (RUT), the first-time absorbance exceeded 0.05 in the reaction. We next determined the cutoff value and calculated accuracy, sensitivity, specificity, positive prediction value (PPV), and negative prediction value (NPV) for each marker evaluation. The IFIT1 scored the best performance at 92.5% sensitivity, but specificity was 77.5%, suggesting that it is difficult to eliminate false positives. We then developed a machine learning model trained with RUT of each marker combination to predict pregnancy. The model created with the RUT of IFIT1 and MUC16 combination showed high specificity (86.7%) and sensitivity (93.3%), which were higher compared to IFIT1 alone. In conclusion, using VMM with RT-LAMP and machine learning algorithm can be used for early pregnancy detection before the return of first estrus., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Ovarian cancer (OC) is the most lethal gynaecological cancer. It is often diagnosed at an advanced stage with poor chances for successful treatment. An accurate blood test for the early detection of OC could reduce the mortality of this disease., Methods: Autoantibody reactivity to 20 epitopes of BARD1 and concentration of cancer antigen 125 (CA125) were assessed in 480 serum samples of OC patients and healthy controls. Autoantibody reactivity and CA125 were also tested for 261 plasma samples of OC with or without mutations in BRCA1/2 , BARD1 , or other predisposing genes, and healthy controls. Lasso statistic regression was applied to measurements to develop an algorithm for discrimination between OC and controls. Findings and interpretation: Measurement of autoantibody binding to a number of BARD1 epitopes combined with CA125 could distinguish OC from healthy controls with high accuracy. This BARD1-CA125 test was more accurate than measurements of BARD1 autoantibody or CA125 alone for all OC stages and menopausal status. A BARD1-CA125-based test is expected to work equally well for average-risk women and high-risk women with hereditary breast and ovarian cancer syndrome (HBOC). Although these results are promising, further data on well-characterised clinical samples shall be used to confirm the potential of the BARD1-CA125 test for ovarian cancer screening.

Several transmembrane mucins have demonstrated that they contribute intracellularly to induce fibrotic processes. The extracellular domain of MUC16 is considered as a biomarker for disease progression and death in IPF patients. However, there is no evidence regarding the signalling capabilities of MUC16 that contribute to IPF development. Here, we demonstrate that MUC16 was overexpressed in the lung tissue of IPF patients ( n = 20) compared with healthy subjects ( n = 17) and localised in fibroblasts and hyperplastic alveolar type II cells. Repression of MUC16 expression by siRNA-MUC16 transfection inhibited the TGF-β1-induced fibrotic processes such as mesenchymal/ myofibroblast transformations of alveolar type II A549 cells and lung fibroblasts, as well as fibroblast proliferation. SiRNA-MUC16 transfection also decreased the TGF-β1-induced SMAD3 phosphorylation, thus inhibiting the Smad Binding Element activation. Immunoprecipitation assays and confocal immunofluorescence showed the formation of a protein complex between MUC16/p-SMAD3 in the cell membrane after TGF-β1 stimulation. This study shows that MUC16 is overexpressed in IPF and collaborates with the TGF-β1 canonical pathway to induce fibrotic processes. Therefore, direct or indirect targeting of MUC16 could be a potential drug target for human IPF.

Purpose: A randomized phase III study evaluated the efficacy of eribulin versus dacarbazine in patients with advanced liposarcoma and leiomyosarcoma. Improved overall survival (OS) led to approval of eribulin for liposarcoma, but not for leiomyosarcoma., Experimental Design: We explored the molecular profile of 77 archival leiomyosarcoma samples from this trial to identify potential predictive biomarkers, utilizing low-coverage whole-genome and whole-exome sequencing. Tumor molecular profiles were correlated with clinical data, and disease control was defined as complete/partial response or stable disease (RECIST v1.1)., Results: Overall, 111 focal copy-number alterations were observed in leiomyosarcoma. Gain of chromosome 17q12 was the most common event, present in 43 of 77 cases (56%). In the eribulin-treated group, gains of 4q26, 20p12.2, 13q13.3, 8q22.2, and 8q13.2 and loss of 1q44 had a negative impact on progression-free survival (PFS), while loss of 2p12 correlated with better prognosis. Gains of 4q22.1 and losses of 3q14.2, 2q14.1, and 11q25 had a negative impact on OS in patients with leiomyosarcoma receiving eribulin. The most commonly mutated genes were TP53 (38%), MUC16 (32%), and ATRX (17%). The presence of ATRX mutations had a negative impact on PFS in both treatment arms; however, the correlation with worse OS was observed only in the eribulin-treated patients. TP53 mutations were associated with longer PFS on eribulin., Conclusions: Leiomyosarcoma has a complex genetic background, with multiple copy-number alterations and mutations affecting genes implicated in tumorigenesis. We identified several molecular changes with potential impact on survival of patients with leiomyosarcoma when treated with eribulin., (©2021 American Association for Cancer Research.)

Colorectal cancer (CRC) remains one of the leading causes of cancer-related death worldwide. The high mortality of CRC is related to its ability to metastasize to distant organs. The kallikrein-related peptidase Kallikrein 6 (KLK6) is overexpressed in CRC and contributes to cancer cell invasion and metastasis. The goal of this study was to identify KLK6-associated markers for the CRC prognosis and treatment. Tumor Samples from the CRC patients with significantly elevated KLK6 transcript levels were identified in the RNA-Seq data from Cancer Genome Atlas (TCGA) and their expression profiles were evaluated using Gene Ontology (GO), Phenotype and Reactome enrichment, and protein interaction methods. KLK6-high cases had a distinct spectrum of mutations in titin ( TTN ), APC , K-RAS , and MUC16 genes. Differentially expressed genes (DEGs) found in the KLK6-overexpressing CRCs were associated with cell signaling, extracellular matrix organization, and cell communication regulatory pathways. The top KLK6-interaction partners were found to be the members of kallikrein family (KLK7, KLK8, KLK10), extracellular matrix associated proteins (keratins, integrins, small proline rich repeat, S100A families) and TGF-β, FOS, and Ser/Thr protein kinase signaling pathways. Expression of selected KLK6-associated genes was validated in a subset of paired normal and tumor CRC patient-derived organoid cultures. The performed analyses identified KLK6 itself and a set of genes, which are co-expressed with KLK6, as potential clinical biomarkers for the management of the CRC disease.

MUC16 (the cancer antigen CA125) is the most commonly used serum biomarker in epithelial ovarian cancer, with increasing levels reflecting disease progression. It is a transmembrane glycoprotein with multiple isoforms, undergoing significant changes through the metastatic process. Aberrant glycosylation and cleavage with overexpression of a small membrane-bound fragment consist MUC16-related mechanisms that enhance malignant potential. Even MUC16 knockdown can induce an aggressive phenotype but can also increase susceptibility to chemotherapy. Variable MUC16 functions help ovarian cancer cells avoid immune cytotoxicity, survive inside ascites and form metastases. This review provides a comprehensive insight into MUC16 transformations and interactions, with description of activated oncogenic signalling pathways, and adds new elements on the role of its differential glycosylation. By following the journey of the molecule from pre-malignant states to advanced stages of disease it demonstrates its behaviour, in relation to the phenotypic shifts and progression of ovarian cancer. Additionally, it presents proposed differences of MUC16 structure in normal/benign conditions and epithelial ovarian malignancy., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aberrant expression of CA125/MUC16 is associated with pancreatic ductal adenocarcinoma (PDAC) progression and metastasis. However, knowledge of the contribution of MUC16 to pancreatic tumorigenesis is limited. Here, we show that MUC16 expression is associated with disease progression, basal-like and squamous tumor subtypes, increased tumor metastasis, and short-term survival of PDAC patients. MUC16 enhanced tumor malignancy through the activation of AKT and GSK3β oncogenic signaling pathways. Activation of these oncogenic signaling pathways resulted in part from increased interactions between MUC16 and epidermal growth factor (EGF)-type receptors, which were enhanced for aberrant glycoforms of MUC16. Treatment of PDAC cells with monoclonal antibody (mAb) AR9.6 significantly reduced MUC16-induced oncogenic signaling. mAb AR9.6 binds to a unique conformational epitope on MUC16, which is influenced by O-glycosylation. Additionally, treatment of PDAC tumor-bearing mice with either mAb AR9.6 alone or in combination with gemcitabine significantly reduced tumor growth and metastasis. We conclude that the aberrant expression of MUC16 enhances PDAC progression to an aggressive phenotype by modulating oncogenic signaling through ErbB receptors. Anti-MUC16 mAb AR9.6 blocks oncogenic activities and tumor growth and could be a novel immunotherapeutic agent against MUC16-mediated PDAC tumor malignancy., Competing Interests: Declaration of interests M.A.H. and P.R. have an equity interest in OncoCare Therapeutics. R.M. is employed by Quest PharmaTech and has an equity interest in this company. All other authors declare no competing interests., (Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

As a common malignancy in females with a higher incidence rate, epithelial ovarian cancer (EOC) is a heterogeneous disease with complexity and diversity in histology and therapeutic response. Although great progress has been made in diagnosis and therapeutic strategies, novel therapeutic strategies are required to improve survival. Although the promoting effect of mucin 16 (MUC16) on tumour progression has been reported, the potential mechanisms remain unclear. In our study, we reported that overexpression of MUC16 was significantly related to cell proliferation and disease progression in EOC. Results from clinical specimen analysis and cell experiment support this conclusion. Patients with a high MUC16 expression usually had a worse prognosis that those with a low expression. Cell proliferation ability was significantly decreased in EOC cell lines when the knockdown of MUC16. Further study shows that the function of MUC16 in cell proliferation is based on the regulation of glucose transporter 1 (GLUT1) expression. MUC16 can control glucose uptake by regulating GLUT1 in EOC cells, thereby promoting glycogen synthesis, so that tumour cells produce more energy for proliferation. This conclusion is based on two findings. First, the significant correlation between MUC16 and GLUT1 was verified by clinical specimen and TCGA data analysis. Then, alteration of MUC16 expression levels can affect the expression of GLUT1 and glucose uptake was also verified. Finally, this conclusion is further verified in vivo by tumour-bearing mice model. To summarize, our results suggest that MUC16 promotes EOC proliferation and disease progression by regulating GLUT1 expression., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Gall bladder carcinoma is endemic in North India along the Ganges belt. Most of the cases usually present in late stage when prognosis is poor. That mandates a necessity for proper screening in these areas for gall bladder lesions. Tumor markers CA 19-9 and CA 125 have been studied in various GI cancers and may also help in the screening, diagnosis and evaluation of gall bladder carcinoma. Aims: To assess serum CA19-9 and serum CA125 in patients with gall bladder lesions and find out a cut off value for diagnosis of carcinoma gallbladder., Methods and Material: Study included 118 cases, with female: male ratio of 4:1.Out of it, 91 (77 %) cases were benign and 27 (23 %) were malignant. Patients' sera was collected and analyzed for CA19-9 and CA 125 by CMIA method., Results: The Mean (SD) value of CA19-9 for benign and malignant cases was found to be 12.86 (17.54) and 625.35(186.52) U/ml. For CA 125 it was found to be 17.98(13.69) and 239.63(73.72) U/ml respectively. The difference was statistically significant (P< 0.001). When Mean - 2SD value of malignant lesions were taken as cut off a value of CA 19-9 and CA 125 were found be 252.31 U/ml & 92.19U/ml respectively, found to be significant to suggest /diagnose a case of carcinoma gall bladder along with clinicoradiological findings. Taking these value as cut off Sensitivity & Specificity for CA 19-9 and CA 125 in detecting malignant cases were found to be 100% & 98.90% and 100% & 94.50% respectively., Conclusions: It is concluded that both serum CA 19-9 and serum CA 125 may act as a good adjunct for diagnosis of cases of carcinoma gallbladder along with imaging studies. However, changes in CA19-9 are more significant than CA 125.

The MUC16 C-terminal (MUC16c) level is associated with tumor serum CA-125 levels, however, the roles remain unclear in gallbladder carcinoma (GBC). In this study, we found that MUC16c promoted glucose uptake and glycolysis for GBC cell proliferation. Mass spectrometry analysis suggested that MUC16c could combine with aldolase. The ALDOC mRNA and protein are overexpressed in GBC tumors. The IHC results also showed the consistent up-regulation of. ALDOC and MUC16c level in GBC tumor tissues than in peritumor tissues. We determined that MUC16c combining with ALDOC promoted ALDOC protein stability and disrupted the ability of ALDOC sensing glucose deficiency, which activated AMPK pathway and increased GBC cell proliferation. ALDOC knockdown significantly inhibited the glucose uptake and glycolysis induced by MUC16c. Our study established important roles of MUC16c promoting GBC cell glycolysis and proliferation and revealed the underlying mechanism of CA-125-related heavy tumor metabolic burden in GBC., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: MUC16 is a mucin marker that is frequently mutated in melanoma, but whether MUC16 mutations could be useful as a surrogate biomarker for tumor mutation burden (TMB) remains unclear., Methods: This study rigorously evaluates the MUC16 mutation as a clinical biomarker in cutaneous melanoma by utilizing genomic and clinical data from patient samples from The Cancer Genome Atlas (TCGA) and two independent validation cohorts. We further extended the analysis to studies with patients treated with immunotherapies., Results: Analysis results showed that samples with MUC16 mutations had a higher TMB than the samples of wild-type, with strong statistical significance ( P < 0.001) in all melanoma cohorts tested. Associations between MUC16 mutations and TMB remained statistically significant after adjusting for potential confounding factors in the TCGA cohort [OR, 9.28 (95% confidence interval (CI), 5.18-17.39); P < 0.001], Moffitt cohort [OR, 31.95 (95% CI, 8.71-163.90); P < 0.001], and Yale cohort [OR, 8.09 (95% CI, 3.12-23.79); P < 0.01]. MUC16 mutations were also found to be associated with overall survival in the TCGA [HR, 0.62; (95% CI, 0.45-0.85); P < 0.01] and Moffitt cohorts [HR, 0.49 (95% CI, 0.28-0.87); P = 0.014]. Strikingly, MUC16 is the only top frequently mutated gene for which prognostic significance was observed. MUC16 mutations were also found valuable in predicting anti-CTLA-4 and anti-PD-1 therapy responses., Conclusions: MUC16 mutation appears to be a useful predictive marker of global TMB and patient survival in melanoma., Impact: This is, to the best of our knowledge, the first systematic evaluation of MUC16 mutation as a clinical biomarker and a predictive biomarker for immunotherapy in melanoma., (©2020 American Association for Cancer Research.)

Importance: As the third most frequently mutated gene in cancers, the association between MUC16 mutation and response to immune checkpoint inhibitors (ICIs) in solid tumors remains unclear., Objective: To examine whether MUC16 mutation is associated with genomic factors in ICI response in solid tumors and with outcomes in ICI-treated patients., Design, Setting, and Participants: This cohort study used multidimensional genomic data of 10 195 patients from The Cancer Genome Atlas (TCGA) across 30 solid tumor types, 56 patients from a non-small cell lung cancer (NSCLC) cohort, and 145 patients from a melanoma cohort. Genomic factors associated with ICI response covered tumor mutational burden, neoantigens, immune-related gene signatures, and tumor immune microenvironment. Both NSCLC and melanoma cohorts included ICI-treated patients. The TCGA cohort was used to examine the association of MUC16 mutation with genomic factors. Two ICI-treated cohorts were used to explore the significance of outcomes associated with MUC16 mutation, using Kaplan-Meier curves and Cox models with adjusting for potential confounders. Gene set enrichment analysis was used to identify MUC16 mutation-associated biological processes. Data were obtained from October 1 through October 10, 2019, and were analyzed from October 11 through December 31, 2019., Main Outcomes and Measures: Genomic factors associated with ICI response, overall survival, and clinical response., Results: Of the 10 195 patients, 4821 (47.6%) were men (median [interquartile range {IQR}] age, 60 [50-70] years). MUC16 was mutated in 2006 of 10 195 patients (19.68%). In this pan-cancer data set, patients with MUC16 mutation had higher tumor mutational burden (median [IQR], 230 [93-595] mutations vs 48 [25-92] mutations; difference, 182 mutations; 95% CI, 164-199 mutations; P < .001) and neoantigen load (median [IQR], 179 [74-394.5] neoantigens vs 48 [24-89] neoantigens; difference, 131 antigens; 95% CI, 116.5-145 neoantigens; P < .001) than those without mutations. The tumor immune microenvironment with dual-positive CD8A and PD-L1 was overrepresented in MUC16-mutated tumors compared with wild-type ones (43.8% vs 32.4%; odds ratio, 1.63; 95% CI, 1.46-1.80; P < .001). Of the 40 immune-related genes, 37 (92.5%) exhibited differential expression between 2 states. MUC16 mutation was associated with improved overall survival in both the NSCLC (hazard ratio, 0.34; 95% CI, 0.12-0.99; P = .04) and melanoma (hazard ratio, 0.57; 95% CI, 0.36-0.90; P = .02) cohorts. The improvement persisted after adjusting for age, sex, and dominant mutational signatures in the melanoma cohort (hazard ratio, 0.57; 95% CI, 0.33-0.96; P = .04). MUC16 mutation was associated with greater response rates in the NSCLC cohort (odds ratio, 4.03; 95% CI, 1.06-16.43; P = .03) and the melanoma cohort (odds ratio, 3.38; 95% CI, 1.07-14.25; P = .03). Gene set enrichment analysis revealed that gene sets regarding cell proliferation and immune response were enriched in MUC16-mutated tumors (false discovery rate, <.001)., Conclusions and Relevance: MUC16 mutation appears to be associated with reported genomic factors associated with response to and improved outcomes for ICI treatment in solid tumors. It may hold promise as a marker for guiding immunotherapeutic responsiveness.

Immunotherapies have dramatically improved survival outcome for patients with melanoma. MUC16 encodes cancer antigen 125 (CA125), which is frequently mutated in melanoma. In this study, we correlated the MUC16 mutational status with the following: tumor mutation burden (TML), multiple immune-related signals in microenvironment, deregulated pathways, survival outcome, and immunotherapeutic efficacy. We found that patients with MUC16 mutations had significantly higher TML than those without it. Enriched pro-inflammatory CD8 T cells and M1 macrophages, enhanced interferon gamma (IFNγ) and T cell-inflamed signatures, and increased cytolytic activity were associated with MUC16 mutations. Immune-suppressive M2 macrophages were enriched in patients with wild-type MUC16 . Immune checkpoints expression (e.g., PD-L1 , PD-1 and CTLA-4 ) was also elevated in patients with MUC16 mutations. Immune response relevant circuits were among the top enriched pathways in samples with MUC16 mutations. Patients with MUC16 mutations exhibited a significantly better prognosis. For patients who received immunotherapy, the presence of MUC16 mutations was associated with a better response rate and survival outcome in male patients but not in female or overall patients. These findings provide new implications for tailoring immunotherapeutic strategies for melanoma patients.

Vitreo-retinal (VR) surgeries induce conjunctival changes. However, there are no study reports regarding prevalence and severity of dry eye after these surgeries. This study evaluated dry eye outcome after VR surgery. Patients undergoing VR surgery classified as scleral buckle and microincision vitrectomy surgery (n = 44, mean age: 56.09±10.2 years) were recruited. Dry eye evaluation was done before and 8 weeks after surgery (2 weeks after omitting topical eye drops). Conjunctival imprint cytology for goblet cell count and tear Mucin 5AC (MUC5AC) protein estimation was done. Gene expressions of MUC5AC, MUC4, MUC16, Aquaporin 4 (AQP4) and AQP5 were analyzed in the conjunctival imprint cells by qPCR. None of the patients exhibited clinical signs of dry eye after VR surgery. But the conjunctival goblet cell density (GCD) was significantly lowered post-VR surgery (63% cases, **p = 0.012) with no alterations in the tear MUC5AC protein. Post-VR surgery, the conjunctival cell gene expression of MUC4, MUC16 and AQP4 were significantly increased (*p = 0.025, *p = 0.05 and *p = 0.02 respectively) and AQP5 was significantly lowered (*p = 0.037), with no change in MUC5AC expression. Tear cytokines were significantly increased post-VR surgery (anti-inflammatory: IL1RA, IL4, IL5, IL9, FGF; PDGFbb and pro-inflammatory: IL2, IL6, IL15, GMCSF and IFNg). Though clinical signs of dry eye were not observed after VR surgery, ocular surface changes in the form of reduced GCD, altered MUC5AC, MUC4, MUC16, AQP4, AQP5 and cytokines are suggestive of dry eye outcome at the molecular level especially inpatients aged above 51 years, especially female gender and those who are diabetic., Competing Interests: The authors have read the journal’s policy and have the following conflicts: Novartis Healthcare Private Limited funded this project. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Purpose: To examine the expression of MUC16 in the endometrium peri-implantation period in three different cohort studies., Methods: This was a retrospective observational cohort study. A total of 245 participants were recruited in three separate cohort studies: (1) women with recurrent miscarriage (n = 50) and fertile controls (n = 29); (2) women who had high (n = 20) or normal (n = 20) progesterone on the day of hCG trigger in ovarian stimulation cycle for IVF; and (3) women who did (n = 95) or did not (n = 31) conceive following frozen embryo transfer in HRT cycles. All subjects had archived endometrial samples precisely taken on LH+7 in natural cycles, or hCG+6 in ovarian stimulation cycles, or P+5 in HRT cycles. The H-score (median, range) of MUC16 in the luminal epithelium and glandular epithelium was determined by using immunohistochemistry., Results: The median (range) of H-score of MUC16 in the luminal epithelium (1) in women with recurrent pregnancy loss was 23.7 (0-300), which was significantly (P < 0.05) lower than that of 118.4 (7.7-300) in fertile controls; (2) in women with elevated progesterone on the day of hCG administration (147.8, 18.0-230.1), significantly (P < 0.05) higher than that of women with normal progesterone (61.0, 2.3-205.3); (3) in women who conceived (23.1, 0-250.3), significantly (P < 0.001) lower than that in women who did not conceive (58.4, 0-300)., Conclusion: The expression of MUC16 in all three cohort studies is consistent with it being an inhibitor of implantation.

Fibrolamellar carcinoma (FLC) is a rare, therapeutically intractable liver cancer that disproportionately affects youth. Although FLC tumors exhibit a distinct gene expression profile, the chromatin regulatory landscape and the genes most critical for tumor cell survival remain unclear. Here, we use chromatin run-on sequencing to discover ∼7,000 enhancers and 141 enhancer hotspots activated in FLC relative to nonmalignant liver. Bioinformatic analyses reveal aberrant ERK/MEK signaling and candidate master transcriptional regulators. We also define the genes most strongly associated with hotspots of FLC enhancer activity, including CA12 and SLC16A14. Treatment of FLC cell models with inhibitors of CA12 or SLC16A14 independently reduce cell viability and/or significantly enhance the effect of the MEK inhibitor cobimetinib. These findings highlight molecular targets for drug development, as well as drug combination approaches., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Circular RNA (circRNA) has been proven to play a significant role in multiple types of cancer. However, the expression and role of circRNAs in epithelial ovarian cancer (EOC) remains elusive., Methods: CircRNA and mRNA expression profiles of EOC were screened with sequencing analysis. Gene silencing and over-expression were used to study circRNA function. Cell proliferation and Matrigel invasion assays were used to detect cell proliferation and invasion, respectively. The expression of circRNAs, mRNAs and miRNAs was detected using qPCR. The location of circRNAs was detected using FISH. The expression of proteins was detected using western blot and immunohistochemistry., Results: CircMUC16 had increased expression in EOC tissues as compared to healthy ovarian tissues. The expression of circMUC16 was linked to the progression in stage and grade of EOC. Hence, silencing circMUC16 suppressed autophagy flux of SKOV3 cells. In contrast, ectopic expression of circMUC16 promoted autophagy flux of A2780 cells. CircMUC16-mediated autophagy exacerbated EOC invasion and metastasis. Mechanistically, circMUC16 could directly bind to miR-199a-5p and relieve suppression of target Beclin1 and RUNX1. In turn, RUNX1 elevated the expression of circMUC16 via promotion of its transcription. CircMUC16 could directly bind to ATG13 and promote its expression., Conclusion: This study demonstrated that circMUC16 regulated Beclin1 and RUNX1 by sponging miR-199a-5p. The data suggested that circMUC16 could be a potential target for EOC diagnosis and therapy.

Objectives: MUC16 (mucin 16, also known as CA-125, cancer antigen 125, carcinoma antigen 125, or carbohydrate antigen 125) has been predicted as tumor biomarker for therapy. We determined to investigate effects and regulatory mechanism of MUC16 on cervical tumorigenesis., Methods: Expression levels of MUC16 in cervical cancer cell lines was analyzed via qRT-PCR (quantitative real-time polymerase chain reaction). Knockdown of MUC16 was conducted via shRNA (Short hairpin RNA) transfection. MTT and colony formation assays were used to investigate effect of MUC16 on cell proliferation. Wound healing assay was utilized to detect migration and transwell assay to detect invasion. The underlying mechanism was demonstrated via western blot analysis., Results: MUC16 was elevated in cervical cancer cell lines. MUC16 knockdown inhibited cell proliferation, invasion and migration. Gain- and loss-of functional assays revealed that over-expression of MUC16 activated Janus Kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) via phosphorylation, thus facilitating cyclooxygenase-2 (COX-2) expression, while knockdown of MUC16 demonstrated the reverse effect on JAK2/STAT3 activation and COX-2 expression. Moreover, inhibition of JAK2/STAT3 attenuated the regulation of MUC16 on COX-2., Conclusions: MUC16 enhanced proliferation and invasion of cervical cancer cells via JAK2/STAT3 phosphorylation-mediated cyclooxygenase-2 expression, suggesting the potential therapeutic target ability of MUC16 to treat cervical cancer.

Background: The occurrence of catamenial pneumothorax (CP) is rare, and the awareness of this diagnosis among physicians is insufficient. CP is highly correlated with pelvic endometriosis and remains the most common form of thoracic endometriosis syndrome. Circulating endometrial cells (CECs) have been previously detected in patients with pelvic endometriosis. Could CECs bring new insights into pneumothorax management?, Methods: This study aims to describe the occurrence and molecular characteristics of CECs in women with spontaneous pneumothorax (SP) (N = 20) with high suspicion of its catamenial character. CECs were enriched from peripheral blood by size-based separation (MetaCell). In addition to cytomorphology, gene expression profiling of captured cells was performed for 24 endometriosis-associated genes., Results: CECs were present in all 20 patients with SP. Enriched CECs exhibited four character features: epithelial, stem cell-like, stroma-like, and glandular. However, not all of them were present in every sampling. Gene expression profiling revealed two distinct phenotypes of CECs in SP and/or CP: one of them refers to the diaphragm openings syndrome and the other to endometrial tissue pleural implantations. Comparisons of the gene expression profiles of CECs in pneumothorax (CECs-SP group) with CECs in pelvic endometriosis (CECs-non-SP group) have revealed significantly higher expression of HER2 in the CECs-SP group compared with the CECs-non-SP group., Conclusions: This proof-of-concept study demonstrates successful isolation and characterization of CECs in patients with SP. Identification of CECs in SP could alert endometriosis involvement and help early referral to gynecologic consultation for further examination and treatment., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Pre-harvest burning of sugarcane fields produces large amounts of air pollutants which are known to cause health problems, including ocular surface abnormalities. In this study, we evaluated the effect of biomass burning on mucus quality and mucin gene expression (MUC1, MUC5AC, MUC16) in the conjunctiva of sugarcane workers (SWs) and residents of an adjacent town (RTs). Impression cytology samples of the inferior tarsal and bulbar conjunctiva of 78 SWs and 32 RTs were collected before (T1) and immediately after (T2) a 6-month harvest period. The neutral, acid and total mucus content of goblet cells was determined by PAS and AB staining. The levels of MUC5AC, MUC1 and MUC16 mRNA in the conjunctiva were measured by real-time PCR. Compared to RTs, SWs had higher levels of bulbar acid mucus and MUC16 mRNA and tarsal MUC5AC mRNA at T2 and lower levels of neutral mucus at T1 and T2. In the SW group, MUC1 mRNA levels were higher at T2 than at T1, but the levels of neutral and acid mucus were similar. In the RT group, acid mucus decreased and neutral mucus increased in the bulbar and tarsal conjunctiva at T2. In conclusion, our findings show that sugarcane harvesting is associated with abnormalities in mucus quality and content and changes in mucin mRNA levels on the ocular surface. This may help explain the ocular inflammatory signs and symptoms observed in subjects exposed to air pollutants and high temperatures from sugarcane biomass burning., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: The relationship of lung adenocarcinoma (LUAD)-specific proteases and the mutant profile of cytoskeletal and extracellular matrix proteins (CECMPs) are examined., Experimental Design: Mutant CECMPs are assessed with an automated application of a protease binding, amino acid-based, scoring database., Results: MUC16 (Human Genome Organization symbol for mucin-16 gene) mutants in particular are, more often than not, resistant to matrix-metalloproteases (MMPs) commonly secreted by LUAD cells, and LUAD cases representing the MUC16, MMP resistant mutants have a worse outcome. Similar results are obtained for MUC16 mutants resistant to cathepsins, also commonly secreted by LUAD cells. Analyses also show that MUC16, MMP resistant peptide mutants have greater binding affinities to HLA-A and HLA-B when compared to MUC16, MMP nonresistant peptide mutants., Conclusion: These results provide a potential, novel biomarker for lung cancer progression, in particular, protease resistant MUC16 peptides; and suggest a possible mechanism of immune escape entailing the reduction of mutant peptides available for HLA class I binding., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: To establish a radiomic model for predicting lymph node (LN) metastasis in patients with non-small cell lung cancer (NSCLC)., Methods: The prediction model was developed using a training cohort comprising 100 patients with clinicopathologically confirmed NSCLC. Data were gathered from January 2014 to December 2015. Radiomic features of NSCLC were obtained from non-contrast and enhancement computed tomography (CT). Lasso-logistic regression models were established for data dimension reduction, feature selection, and radiomics signature building. Consistency coefficient ( ICC s) was used to evaluate the consistency between observer interior and interobserver.The consistency index （C-index）is used to evalutate the prediction of lymph node metastasis by using the radiomics signature, shown with the area under the receiver operating characteristic curve ( AUC ).Multivariate logistic regression analyses were performed to develop the prediction model, considering radiomics signature and clinicopathologic risk factors. The radiomics model was validated in a validation cohort comprising 100 consecutive NSCLC patients from January 2016 to December 2017 in terms of its calibration and discrimination. AUC was used to evaluate the predictive effectiveness of the model, and Delong test was used to compare models. Hosmer-Lemeshow good of fit test was used to evaluate the calibration of prediction models.The results were represented by correction curves to compare the consistency between the predicted results of the model and the actual probability of LN metastasis., Results: The consistency between observer interior and interobserver was good, with ICCs higher than 0.75.The radiomics signature, including 22 selected features, was associated with LN metastasis. AUC was 0.781 in training cohort and 0.776 in validation cohort. The individualized prediction model identified radiomics signature, neuron specific enolase (CEA), cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), and carbohydrate antigen 125 (CA125) as independent predictors. The model showed good discrimination, with 0.836 AUC in the training cohort, and 0.821 AUC in the validation cohort. The model in both the training and validation cohorts had good calibration,which demonstrated high consistency with the actual LN metastasis., Conclusion: The radiomics model incorporating radiomics signature and clinical risk factors can be conveniently used to facilitate preoperative individualized prediction of LN metastasis in patients with NSCLC., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Science Edition).)

Background: CA125 is a well-established ovarian cancer (OC) serum biomarker. The CA125 heavily glycosylated epitope is carried by the MUC16 mucin, a high molecular weight transmembrane mucin. Upon proteolytic cleavage, the extracellular domain of MUC16 is released from the cell surface into malignant ascites and blood vessels. Previous studies have shown that both tumor and surrounding mesothelial cells may express MUC16. Although little is known about the regulation of MUC16 expression in these cells, recent evidence suggest that inflammatory cytokines may stimulate MUC16 expression. Because malignant ascites is a pro-inflammatory environment, we investigated whether OC ascites stimulate the expression and release of MUC16 by human peritoneal mesothelial cells (HPMCs)., Methods: HPMCs were isolated from peritoneal lavages of women operated for conditions other than cancer. MUC16 protein expression was determined by immunoblot, immunofluorescence or immunohistochemistry depending on the experiments. The release of MUC16 from the cell surface was measured using EIA and MUC16 mRNA expression by ddPCR., Results: We show that high-grade serous ascites from patients with OC (n = 5) enhance MUC16 expression in HPMCs. Malignant ascites, but not benign peritoneal fluids, stimulate the release of MUC16 in HPMCs in a dose-dependent manner, which is abrogated by heat inactivation. Moreover, we establish that ascites-induced MUC16 expression occurs at the post-transcriptional level and demonstrate that ascites-induced MUC16 expression is mediated, at least partially, through an Akt-dependent pathway. A cytokine array identified upregulation of several cytokines and chemokines in ascites that mediate MUC16 upregulation versus those that do not, including CCL7, CCL8, CCL16, CCL20, CXCL1, IL-6, IL-10, HGF and IL-1 R4. However, when individually tested, none of these factors affected MUC16 expression or secretion. Concentrations of CA125 in the serum of a given patient did not correlate with the ability of its corresponding ascites to stimulate MUC16 release in HPMCs., Conclusions: Collectively, these data indicate that mesothelial cells are an important source of MUC16 in the context of ovarian cancer and malignant ascites is a strong modulator of MUC16 expression in HPMCs and uncover the Akt pathway as a driving factor for upregulation of MUC16. Factors in ascites associated with enhanced MUC16 expression and release remains to be identified.

Background: Epithelial ovarian cancer (EOC) remains one of the most lethal gynecologic cancers, and its pathogenetic mechanism remains unclear. Here we show that MUC16 promotes the translocation of p120-catenin (p120ctn) to the cytoplasm and consequently activates ras homolog (Rho) GTPases RhoA/Cdc42 activation to modulate the proliferation and migration abilities of EOC cells., Methods: We collect 94 ovarian cancer (OC) patients' tissue samples to constitute tissue microarray (TMA) and analyze the MUC16 and p120ctn expression levels. Lentivirus transfection is used to overexpress cytoplasmic tail domain (CTD) of MUC16 and CRISPR/Cas9 genome-editing system is firstly used to knock out MUC16 in EOC cells. The proliferation or migration ability of cells is analyzed by MTS or migration assay., Results: We find that MUC16 and p120ctn are aberrantly overexpressed in 94 clinical OC samples compared with benign ovarian tumors (BOT). MUC16 is a critical inducer of the proliferation and migration of EOC cells and the CTD of MUC16 plays an important role during this process. In addition, we reveal the relationship between MUC16 and p120ctn, which has not previously been studied. We show that MUC16 promotes the translocation of p120ctn to the cytoplasm and consequently activates Rho GTPases to modulate the proliferation and migration abilities of EOC cells. The cell proliferation and migration abilities induced by MUC16 are mediated by p120ctn through RhoA/Cdc42 activation., Conclusions: The highly expressed MUC16 promotes the translocation of p120ctn to the cytoplasm, where it activates RhoA/Cdc42 to modulate the proliferation and migration abilities of EOC cells. These findings may provide new targets for the treatment of EOC.

Tumor markers are noninvasive diagnostic tools for cancer. Their abnormal expression often occurs earlier than clinical symptoms or other detection signals. Appropriate reference intervals (RIs) of tumor markers are important for health evaluation, cancer diagnosis, therapy monitoring and prognosis assessment. In this study, we aimed to establish the RIs of cancer antigen 125 (CA125), CA15-3, CA19-9, CA72-4, alpha fetoprotein (AFP), carcino-embryonic antigen (CEA), neuron-specific enolase (NSE) and cytokeratin 19 fragment antigen 21-1 (CYFRA21-1) in apparently healthy Henan population. A total of 1705 apparently healthy participants (21-89 years) were recruited from five representative geographical regions in Henan province. Nonparametric 95th percentile intervals were used to define the RIs of CA125, CA15-3, CA19-9, CA72-4, AFP, CEA, NSE and CYFRA21-1. The test results of CA125, CA15-3, CA19-9, CA72-4, AFP, CEA, NSE and CYFRA21-1 can traceable to reference measurement procedures. The age- and gender-specific RIs of the tumor markers were established. We established age- and gender-specific RIs for CA125, CA15-3, CA19-9, CA72-4, AFP, CEA, NSE and CYFRA21-1. The newly established RIs should be more suitable for Henan population. It will be valuable for clinicians to make a medical diagnosis, therapeutic management decision and other physiological assessment.

Objective: This study was performed to investigate the diagnostic accuracy of frozen section (FS) of mucinous borderline ovarian tumors (mBOTs) and the diagnostic value of various risk factors for misdiagnosis., Methods: Patients with either an FS or permanent pathologic diagnosis of mBOT were included. Optimum cut-off values for serum tumor markers and maximal tumor diameter were determined, and risk factors for underdiagnosis of mucinous malignant ovarian tumors (mMOTs) were evaluated. The sensitivity, specificity, Youden's index, and diagnostic odds ratio of the risk factors were assessed to determine their diagnostic value for mMOTs., Results: Of 121 included patients, 97 were diagnosed with mBOTs by FS. Relatively abnormal cancer antigen 125 (CA125), carbohydrate antigen 19-9 (CA19-9), and carcinoembryonic antigen (CEA) levels; bilateral tumors; and specific pathological features showed significant associations with underdiagnosis of mMOTs in the univariate analysis. The presence of specific pathological features was the only significant risk factor in the multivariate analysis. The CA125, CA19-9, and CEA levels and specific pathological features demonstrated certain diagnostic value in detecting malignant cases among FS-diagnosed mBOTs., Conclusions: In patients with FS-diagnosed mBOT, significant predictors of malignancy were relatively higher CA125, CA19-9, and CEA levels; bilateral tumors; and tumors with specific pathological features.

Mutations in oncogenes or tumor suppressors can reprogram tumor metabolism by controlling multiple metabolic changes including glycolysis, glutaminolysis, increased autophagy, and macropinocytosis. Somatic mutations are essential for the development and growth of gastric cancer (GC), but the precise roles of these mutations in GC glucose metabolism remain largely unknown. In this study, we examined cancer genomes in 375 GC samples and demonstrated several glycolysis-related mutations in GC. Of note, loss-of-function mutation in MUC16 gene was identified. Mutated MUC16 predicted a better prognosis in GC patients. Gene set enrichment analysis suggested that mutated MUC16 status was associated with down-regulation of PI3K/Akt/mTOR signaling and Myc expression. GC cells with MUC16 mutations had reduced glycolytic capacity. Subsequently, genetic silencing of MUC16 in SNU16 and SNU5 cells led to significant reduction in glucose uptake, lactate production, extracellular acidification rate, and colony formation ability, indicating the critical regulatory roles of MUC16 in GC glycolysis and tumorigenesis. Specifically, western blotting showed that MUC16 knockdown inhibited PI3K/Akt/mTOR signaling, and reduced the protein level of Myc, which acts as a key transcription factor in regulating glycolysis. Taken together, our findings identify the MUC16-PI3K/Akt/mTOR-Myc axis as a critical signaling cascade that couples genomic mutations to metabolic reprogramming in GC., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Importance: MUC16, which encodes cancer antigen 125 (CA-125), is frequently mutated in gastric cancer (GC); however, its association with tumor mutation load (TML) and outcome in patients with GC has not been established, to date., Objective: To investigate whether MUC16 mutations are associated with TML and prognosis in patients with GC., Design, Setting, and Participants: Statistical analysis of genomic data from 437 GC samples obtained from The Cancer Genome Atlas (TCGA) and 256 samples from an Asian cohort. Both cohorts contained data of patients with GC involved in previous genomic studies. Data were obtained from TCGA on September 3, 2017, and from the Asian cohort on March 5, 2013, and analyzed from September 3 to December 1, 2017. The TCGA cohort was used as a discovery set and the Asian cohort as a validation set. Kaplan-Meier survival analysis and multivariate Cox and logistic regression models were applied. Regression models addressed confounding factors; Bayesian variant nonnegative matrix factorization was used to extract mutational signatures. The MutSigCV algorithm was used to identify significantly mutated genes., Main Outcomes and Measures: Primary outcomes were mutation frequency, overall survival, and TML, calculated using Kaplan-Meier survival analysis, odds ratios (ORs), and significance of signaling pathways., Results: MUC16 was mutated in 168 of 437 (38.4%) of the GC samples from the TCGA cohort and in 57 of 256 (22.3%) from the Asian cohort. In both cohorts, GC samples with MUC16 mutations exhibited significantly greater TML than those without MUC16 mutations (median mutation counts: TCGA cohort, 264 with MUC16 mutation vs 115 without; Asian cohort, 134 with MUC16 mutation vs 74 without; Wilcoxon rank sum test, both P < .001). This association was independent of mutations in POLE and BRCA1/2 and mutational signatures in the TCGA cohort (OR, 1.87; 95% CI, 1.49-2.36; P < .001) and the Asian cohort (OR, 1.69; 95% CI, 1.25-2.29; P < .001). MUC16 mutations were significantly associated with better prognosis in both cohorts (median overall survival, 46.9 [95% CI, 26.4-NA (not available)] vs 26.7 [95% CI, 20.2-43.1] months; log-rank test, P = .007 [TCGA cohort] and not calculable [the median overall survival of patients with GC and MUC16 mutations could not be calculated because more than half the patients in the group were alive] vs 36.8 months; P = .04 [Asian cohort]). The association remained statistically significant after controlling for age, sex, TNM stage, mutations in POLE and BRCA1/2, and mutational signatures (hazard ratio, 0.61 [95% CI, 0.42-0.89]; log rank test, P = .01). Immune response and cell cycle regulation circuits were among the top altered signaling pathways in samples with MUC16 mutations (normalized enrichment score, 1.70 [95% CI, 1.57-1.79] and 2.04 [95% CI, 1.90-2.18]; adjusted P < .001). The prognostic significance of MUC16 mutation identified in the TCGA cohort was validated in the Asian cohort., Conclusions and Relevance: These findings indicate that MUC16 mutations may be associated with higher TML, better survival outcomes, and immune response and cell cycle pathways. These findings may be immediately applicable for guiding immunotherapy treatment for patients with GC.

Ovarian cancer is the leading cause of cancer death among gynecological malignancies. The high mortality rate has not been significantly reduced despite advances in surgery and chemotherapy. Gene therapy shows therapeutic potential, but several key issues must be resolved before clinical application. To minimize toxicity in noncancerous tissues, tumor-specific ligands are conjugated to vectors to increase the selectivity of drug delivery. The expression pattern of follicle-stimulating hormone (FSH) receptor in normal and cancer tissues provides an opportunity for highly selective drug delivery in ovarian cancer. Furthermore, tumor-specific promoters can conditionally regulate therapeutic gene expression in tumor or normal tissues. The mucin 16 (MUC16) promoter might be a potential tool to drive ovarian cancer-localized gene expression since MUC16/CA125 is overexpressed in most ovarian carcinomas. Here, we screened the possible MUC16 promoter sequences and constructed MUC16 promoter-driven gro-α shRNA plasmid vectors. The vectors were specifically delivered into ovarian cancer cells via FSH peptide-conjugated nanoparticles. The predicted promoter sequence with TAAA repeats showed high transcriptional activity. The nanoparticle complex containing MUC16 promoter-driven gro-α shRNA and FSH peptides had the ability to decrease gro-α protein secretion in ovarian cancer cells and block tumor growth without obvious toxic effects in a nude mouse model bearing ovarian cancer. Our study provides a novel gene delivery system using a MUC16 promoter trigger and FSH peptide-mediated active targeting in ovarian cancer, and this system may be a promising strategy for specific genetic therapeutic delivery.

New plasma and tissue biomarkers of epithelial ovarian cancer (EOC) could improve early diagnosis and post-diagnosis clinical management. Here we investigated tissue staining and tissue secretion of CLIC1 and CLIC4 across EOC subtypes. CLIC1 and CLIC4 are two promising biomarkers we previously showed were elevated in EOC patient sera. Individually, CLIC1 or CLIC4 stained larger percentages of malignant tumors across all EOC subtypes compared with CA125, particularly early stage and mucinous tumors. CLIC4 also stained benign tumors but staining was limited to nuclei; whereas malignant tumors showed diffuse cellular staining of stromal and tumor cells. Both proteins were shed by all EOC subtypes tumors in short term organ culture at more consistent levels than CA125, supporting their potential as pan-subtype serum and tissue biomarkers. Elevated CLIC4 expression, but not CLIC1 expression, was a negative indicator of patient survival, and CLIC4 knockdown in cultured cells decreased cell proliferation and migration indicating a potential role in tumor progression. These results suggest CLIC1 and CLIC4 are promising serum and tissue biomarkers as well as potential therapeutic targets for all EOC subtypes. This justifies development of high throughput serum/plasma biomarker assays to evaluate utility of a biomarker panel consisting of CLIC1, CLIC4 and CA125.

Background: MUC4 is a membrane-bound mucin that promotes carcinogenetic progression and is often proposed as a promising biomarker for various carcinomas. In this manuscript, we analyzed large scale genomic datasets in order to evaluate MUC4 expression, identify genes that are correlated with MUC4 and propose new signatures as a prognostic marker of epithelial cancers., Methods: Using cBioportal or SurvExpress tools, we studied MUC4 expression in large-scale genomic public datasets of human cancer (the cancer genome atlas, TCGA) and cancer cell line encyclopedia (CCLE)., Results: We identified 187 co-expressed genes for which the expression is correlated with MUC4 expression. Gene ontology analysis showed they are notably involved in cell adhesion, cell-cell junctions, glycosylation and cell signaling. In addition, we showed that MUC4 expression is correlated with MUC16 and MUC20, two other membrane-bound mucins. We showed that MUC4 expression is associated with a poorer overall survival in TCGA cancers with different localizations including pancreatic cancer, bladder cancer, colon cancer, lung adenocarcinoma, lung squamous adenocarcinoma, skin cancer and stomach cancer. We showed that the combination of MUC4, MUC16 and MUC20 signature is associated with statistically significant reduced overall survival and increased hazard ratio in pancreatic, colon and stomach cancer., Conclusions: Altogether, this study provides the link between (i) MUC4 expression and clinical outcome in cancer and (ii) MUC4 expression and correlated genes involved in cell adhesion, cell-cell junctions, glycosylation and cell signaling. We propose the MUC4/MUC16/MUC20 high signature as a marker of poor prognostic for pancreatic, colon and stomach cancers.

Introduction: MUC16 is overexpressed in multiple cancers and plays an important role in tumorigenicity and acquired resistance to therapy. Area covered: In this review, we describe the role of MUC16 under normal physiological conditions and during tumorigenesis. First, we provide a summary of research on MUC16 from its discovery as CA125 to present anti-MUC16 therapy trials that are currently in the initial phases of clinical testing. Finally, we discuss the reasons for the limited effectiveness of these therapies and discuss the direction and focus of future research. Expert opinion: Apart from its protective role in normal physiology, MUC16 contributes to disease progression and metastasis in several malignancies. Due to its aberrant overexpression, it is a promising target for diagnosis and therapy. Cleavage and shedding of its extracellular domain is the major barrier for efficient targeting of MUC16-expressing cancers. Concerted efforts should be undertaken to target the noncleaved cell surface retained portion of MUC16. Such efforts should be accompanied by basic research to understand MUC16 cleavage and decipher the functioning of MUC16 cytoplasmic tail. While previous efforts to activate anti-MUC16 immune response using anti-CA125 idiotype antibodies have met with limited success, ideification of neo-antigenic epitopes in MUC16 that correlate with improved survival have raised raised hopes for developing MUC16-targeted immunotherapy.