Mucin expression, epigenetic regulation and patient survival: A toolkit of prognostic biomarkers in epithelial cancers

Jonckheere, Nicolas; Vincent, Audrey; Neve, Bernadette; Seuningen, Isabelle Van

doi:10.1016/j.bbcan.2021.188538

Cited by 22 publications

(18 citation statements)

References 195 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In PDAC, both MUC4 and miR-210-3p are up-regulated [ 5 , 14 , 15 , 25 ] and associated with poor prognosis [ 15 , 30 ]. In this study, we revealed a positive correlation between Muc4 expression and miR-210-3p during PanIN initiation and progression.…”

Section: Discussionmentioning

confidence: 99%

Antagonistic Roles of the Tumor Suppressor miR-210-3p and Oncomucin MUC4 Forming a Negative Feedback Loop in Pancreatic Adenocarcinoma

Boukrout

Souidi

Lahdaoui

et al. 2021

Cancers

Self Cite

View full text Add to dashboard Cite

Background: Pancreatic adenocarcinoma (PDAC) is a deadly cancer with an extremely poor prognosis. MUC4 membrane-bound mucin is neoexpressed in early pancreatic neoplastic lesions and is associated with PDAC progression and chemoresistance. In cancers, microRNAs (miRNAs, small noncoding RNAs) are crucial regulators of carcinogenesis, chemotherapy response and even metastatic processes. In this study, we aimed at identifying and characterizing miRNAs activated downstream of MUC4-associated signaling in pancreatic adenocarcinoma. MiRnome analysis comparing MUC4-KD versus Mock cancer cells showed that MUC4 inhibition impaired miR-210-3p expression. Therefore, we aimed to better understand the miR-210-3p biological roles. Methods: miR-210-3p expression level was analyzed by RT-qPCR in PDAC-derived cell lines (PANC89 Mock and MUC4-KD, PANC-1 and MiaPACA-2), as well as in mice and patients tissues. The MUC4-miR-210-3p regulation was investigated using luciferase reporter construct and chromatin immunoprecipitation experiments. Stable cell lines expressing miR-210-3p or anti-miR-210-3p were established using CRISPR/Cas9 technology or lentiviral transduction. We evaluated the biological activity of miR-210-3p in vitro by measuring cell proliferation and migration and in vivo using a model of subcutaneous xenograft. Results: miR-210-3p expression is correlated with MUC4 expression in PDAC-derived cells and human samples, and in pancreatic PanIN lesions of Pdx1-Cre; LstopL-KrasG12D mice. MUC4 enhances miR-210-3p expression levels via alteration of the NF-κB signaling pathway. Chromatin immunoprecipitation experiments showed p50 NF-κB subunit binding on miR-210-3p promoter regions. We established a reciprocal regulation since miR-210-3p repressed MUC4 expression via its 3′-UTR. MiR-210-3p transient transfection of PANC89, PANC-1 and MiaPACA-2 cells led to a decrease in cell proliferation and migration. These biological effects were validated in cells overexpressing or knocked-down for miR-210-3p. Finally, we showed that miR-210-3p inhibits pancreatic tumor growth and proliferation in vivo. Conclusion: We identified a MUC4-miR-210-3p negative feedback loop in early-onset PDAC, but also revealed new functions of miR-210-3p in both in vitro and in vivo proliferation and migration of pancreatic cancer cells, suggesting a complex balance between MUC4 pro-oncogenic roles and miR-210-3p anti-tumoral effects.

show abstract

Section: Discussionmentioning

confidence: 99%

Antagonistic Roles of the Tumor Suppressor miR-210-3p and Oncomucin MUC4 Forming a Negative Feedback Loop in Pancreatic Adenocarcinoma

Boukrout

Souidi

Lahdaoui

et al. 2021

Cancers

Self Cite

View full text Add to dashboard Cite

show abstract

“…The two major classifications of mucins are (A) gel-forming and non-gel-forming mucins and (B) membrane-bound and secretory mucins [ 29 ]. These mucins differ in size, domain structures and organizations, glycosylation, and functions [ 28 , 30 , 31 , 32 , 33 ]. Epithelial malignancies are often characterized by deregulated mucin expression [ 31 , 32 ] and their aberrant glycosylation pattern [ 34 , 35 ].…”

Section: Mucin Deregulation In Cancermentioning

confidence: 99%

“…These mucins differ in size, domain structures and organizations, glycosylation, and functions [ 28 , 30 , 31 , 32 , 33 ]. Epithelial malignancies are often characterized by deregulated mucin expression [ 31 , 32 ] and their aberrant glycosylation pattern [ 34 , 35 ]. Concomitant to oncogenic mutations, a loss or gain of mucin expression has been reported in different cancers, including carcinomas of the pancreas, colon, lung, ovary, and breast [ 31 , 36 , 37 , 38 ].…”

Section: Mucin Deregulation In Cancermentioning

confidence: 99%

Mucins as Potential Biomarkers for Early Detection of Cancer

Gautam

Κhan

Gopalakrishnan

et al. 2023

Cancers

View full text Add to dashboard Cite

Early detection significantly correlates with improved survival in cancer patients. So far, a limited number of biomarkers have been validated to diagnose cancers at an early stage. Considering the leading cancer types that contribute to more than 50% of deaths in the USA, we discuss the ongoing endeavors toward early detection of lung, breast, ovarian, colon, prostate, liver, and pancreatic cancers to highlight the significance of mucin glycoproteins in cancer diagnosis. As mucin deregulation is one of the earliest events in most epithelial malignancies following oncogenic transformation, these high-molecular-weight glycoproteins are considered potential candidates for biomarker development. The diagnostic potential of mucins is mainly attributed to their deregulated expression, altered glycosylation, splicing, and ability to induce autoantibodies. Secretory and shed mucins are commonly detected in patients’ sera, body fluids, and tumor biopsies. For instance, CA125, also called MUC16, is one of the biomarkers implemented for the diagnosis of ovarian cancer and is currently being investigated for other malignancies. Similarly, MUC5AC, a secretory mucin, is a potential biomarker for pancreatic cancer. Moreover, anti-mucin autoantibodies and mucin-packaged exosomes have opened new avenues of biomarker development for early cancer diagnosis. In this review, we discuss the diagnostic potential of mucins in epithelial cancers and provide evidence and a rationale for developing a mucin-based biomarker panel for early cancer detection.

show abstract

“…The aberrant expression of the MUC5AC gene, located on chromosome 11p15, has been observed in various malignant conditions, including lung cancer. An increasing body of evidence suggests that MUC5AC is associated with multiple cellular signal pathways, affecting cell proliferation, growth and apoptosis 7–9 . MUC5AC gene expression varies among different subtypes of lung cancer, especially in lung adenocarcinoma, since it may be influenced by distinct signalling pathways involving several genetic alterations.…”

Section: Introductionmentioning

confidence: 99%

“…An increasing body of evidence suggests that MUC5AC is associated with multiple cellular signal pathways, affecting cell proliferation, growth and apoptosis. [7][8][9] MUC5AC gene expression varies among different subtypes of lung cancer, especially in lung adenocarcinoma, since it may be influenced by distinct signalling pathways involving several genetic alterations. Interestingly, KRAS-mutant ADCs are characterized by high MUC5AC expression which correlated with worse clinical outcomes.…”

mentioning

confidence: 99%

Molecular insight of p53/Sp1/MUC5AC axis in the tumorigenesis and progression of lung adenocarcinoma

Zhang

et al. 2022

Clin Exp Pharma Physio

View full text Add to dashboard Cite

The aberrant expression of secretory mucin MUC5AC has been documented during the tumourigenesis and progression of various cancers. However, little is currently known on the function of MUC5AC in lung adenocarcinoma. The present study focused on the tumour‐promoting role of MUC5AC and its regulatory mechanisms in lung adenocarcinoma. Firstly, MUC5AC expression was evaluated in NSCLC tissue microarrays by immunohistochemistry. Kaplan–Meier analysis were used to clarify the prognostic value of MUC5AC. Subsequently, small interfering RNA and small hairpin RNA were used to knockdown MUC5AC in lung ADC cell lines to elucidate its role in tumorigenesis and progression of lung adenocarcinoma via in vitro functional assays and xenograft mouse models. Finally, the regulatory mechanisms underlying p53/Sp1/MUC5AC axis were identified through dual‐luciferase report. We found that MUC5AC was upregulated in lung ADC tissues and cell lines, especially in KRAS‐mutant cases and correlated with poor prognosis. MUC5AC gene silencing resulted in reduced cell proliferation, invasion and migration. Furthermore, knockdown of MUC5AC led to reversion of the epithelial–mesenchymal transition. Additionally, downregulation of MUC5AC reduced tumourigenesis in mouse models. Finally, we found an antagonistic role between Sp1 and p53 in the regulation of MUC5AC gene expression. Our findings suggest that high MUC5AC expression promotes tumourigenesis and progression of lung ADC. Both p53 gene inactivation and Sp1 overexpression in lung ADC may enhance MUC5AC expression, especially in KRAS‐mutated cases. Given the paucity of efficient drug‐targeted approaches of KRAS‐driven lung ADCs, therapies directed at downstream effectors such as MUC5AC could have huge prospects.

show abstract

Mucin expression, epigenetic regulation and patient survival: A toolkit of prognostic biomarkers in epithelial cancers

Cited by 22 publications

References 195 publications

Antagonistic Roles of the Tumor Suppressor miR-210-3p and Oncomucin MUC4 Forming a Negative Feedback Loop in Pancreatic Adenocarcinoma

Antagonistic Roles of the Tumor Suppressor miR-210-3p and Oncomucin MUC4 Forming a Negative Feedback Loop in Pancreatic Adenocarcinoma

Mucins as Potential Biomarkers for Early Detection of Cancer

Molecular insight of p53/Sp1/MUC5AC axis in the tumorigenesis and progression of lung adenocarcinoma

Contact Info

Product

Resources

About