Expression profiles of MUC1, MUC2, and MUC4 mucins in human neoplasms and their relationship with biological behavior

Yonezawa, Suguru; Goto, Masamichi; Yamada, Norishige; Higashi, Michiyo; Nomoto, Mitsuharu

doi:10.1002/pmic.200800040

Cited by 109 publications

(120 citation statements)

References 61 publications

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“…In addition to altering surface properties of tumor cells, several mucin molecules also have intracellular domains that are directly connected to oncogenic signalling pathways (38,39). MUC4 has been reported to be expressed in pancreatic adenocarcinomas but not in adjacent normal tissue (40,41) and was proposed to be a novel tumor marker for this disease as the prognosis of patients with high MUC4 expression was significantly reduced (42). The intracellular domain of MUC4 contains an amino acid sequence that acts as a direct stimulating ligand for the tyrosine kinase receptor erbB2 (43,44).…”

Section: Discussionmentioning

confidence: 99%

Mucin production determines sensitivity to bortezomib and gemcitabine in pancreatic cancer cells

Wissniowski¹

2012

Int J Oncol

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Abstract. The prognosis of pancreatic cancer remains disappointing due to a high intrinsic resistance against chemotherapeutic agents. Standard gemcitabine therapies have improved overall survival only marginally and recently, inhibition of the proteasome by the boronic acid derivative bortezomib has been introduced as a novel therapeutic strategy for solid and hematological malignancies including pancreatic cancer. The mucus-producing pancreatic cancer cell line Capan-1 was cultured under standard conditions and treated with different concentrations of gemcitabine or bortezomib. Mucus production was suppressed by siRNA-mediated silencing of apomucin genes. Cell proliferation was determined by 3 H-thymidine incorporation and apoptosis was quantified after propidium iodide staining by flow cytometry. Apoptotic cell death was confirmed by TUNEL staining, determination of mitochondrial transmembrane potential and assessment of caspase 3/7 activity. NFκB-activity was determined by EMSA. The unfolded protein response (UPR) was further investigated by PCR, Western blotting and caspase 12 activity assays. Silencing of MUC4 significantly reduced expression of mucins for up to 5 days after transfection. While native cells showed an increased sensitivity to bortezomib treatment, silenced cells were more sensitive to gemcitabine treatment. Bortezomib induces mitochondrial damage in native cells and also activates the UPR by splicing of Xbp-1 and induction of CHOP, which is significantly reduced by silencing of MUC4. Our data suggest that mucinous pancreatic cancers are more sensitive towards proteasome inhibition by bortezomib and that alternative pathways of apoptosis are involved in cell death induction, while tumor cells with a low secretory activity show a better response to gemcitabine.

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Section: Discussionmentioning

confidence: 99%

Mucin production determines sensitivity to bortezomib and gemcitabine in pancreatic cancer cells

Wissniowski¹

2012

Int J Oncol

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“…Mucins are high-molecular-weight glycoproteins with oligosaccharides attached to serine or threonine residues of the mucin core protein backbone by O-glycosidic linkages that are produced by various epithelial cells and play a role in cell-cell interactions (Yonezawa et al 2008). MUC genes are highly variable in humans and often contain novel and unique SNVs in germline samples.…”

Section: Mucin As a Possible New Biomarker In Pnetmentioning

confidence: 99%

Whole-exome characterization of pancreatic neuroendocrine tumor cell lines BON-1 and QGP-1

Vandamme¹,

Peeters²,

Dogan³

et al. 2015

Journal of Molecular Endocrinology

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The human BON-1 and QGP-1 cell lines are two frequently used models in pancreatic neuroendocrine tumor (PNET) research. Data on the whole-exome genetic constitution of these cell lines is largely lacking. This study presents, to our knowledge, the first wholeexome profile of the BON-1 and QGP-1 cell lines. Cell line identity was confirmed by short tandem repeat profiling. Using GTG-banding and a CytoSNP-12v2 Beadchip array, cell line ploidy and chromosomal alterations were determined in BON-1 and QGP-1. The exomes of both cell lines were sequenced on Ilumina's HiSeq next-generation sequencing (NGS) platform. Single-nucleotide variants (SNVs) and insertions and deletions (indels) were detected using the Genome Analysis ToolKit. SNVs were validated by Sanger sequencing. Ploidy of BON-1 and QGP-1 was 3 and 4 respectively, with long stretches of loss of heterozygosity across multiple chromosomes, which is associated with aggressive tumor behavior. In BON-1, 57 frameshift indels and 1725 possible protein-altering SNVs were identified in the NGS data. In the QGP-1 cell line, 56 frameshift indels and 1095 SNVs were identified. ATRX, a PNET-associated gene, was mutated in both cell lines, while mutation of TSC2 was detected in BON-1. A mutation in NRAS was detected in BON-1, while KRAS was mutated in QGP-1, implicating aberrations in the RAS pathway in both cell lines. Homozygous mutations in TP53 with possible loss of function were identified in both cell lines. Various MUC genes, implicated in cell signaling, lubrication and chemical barriers, which are frequently expressed in PNET tissue samples, showed homozygous proteinaltering SNVs in the BON-1 and QGP-1 cell lines.

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“…Moreover, the treatment of MCF-7 cancer cells with leptin induced the expression of another diagnostic marker gene, MUC1. MUC1 expression is related to the aggressive behavior of human neoplasm and to poor patient outcome (Yonezawa et al 2008). MUC1 may function as an anti-adhesion molecule enabling invasion into surrounding tissues (Yonezawa et al 2008).…”

Section: Tablementioning

confidence: 99%

Involvement of adiponectin and leptin in breast cancer: clinical and in vitro studies

Jardé

Caldefie-Chézet

Goncalves-Mendès

et al. 2009

Endocrine-Related Cancer

135

121

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Obesity is a risk factor for breast cancer development. A recent hypothesis suggests that the adipokines, adiponectin and leptin, are involved in breast cancer development. This prompted us to investigate the role of adiponectin and leptin in mammary carcinogenesis. Adiponectin receptors (AdipoR1 and AdipoR2) and leptin receptor (Ob-Rt, representing all the isoforms of Ob-R) proteins were detected by immunohistochemistry in in situ ductal carcinoma, invasive ductal malignancy, and healthy adjacent tissue. In addition, mRNA expression of adiponectin, AdipoR1, AdipoR2, leptin, Ob-Rt, and Ob-Rl (the long isoform of Ob-R) was observed in MCF-7 breast cancer cells. Interestingly, leptin mRNA expression was 34.7-fold higher than adiponectin mRNA expression in the MCF-7 cell line. Moreover, adiponectin (10 mg/ml) tended to decrease the mRNA expression of leptin (K36%) and Ob-Rl (K28%) and significantly decreased Ob-Rt mRNA level (K26%). In contrast, leptin treatment (1 mg/ml) significantly decreased AdipoR1 mRNA (K23%). Adiponectin treatment (10 mg/ml) inhibited the proliferation of MCF-7 cells, whereas leptin (1 mg/ml) stimulated the growth of cancer cells. In addition, adiponectin inhibited leptin-induced cell proliferation (both 1 mg/ml). Using microarray analysis, we found that adiponectin reduced the mRNA levels of genes involved in cell cycle regulation (mitogen-activated protein kinase 3 and ATM), apoptosis (BAG1, BAG3, and TP53), and potential diagnosis/prognosis markers (ACADS, CYP19A1, DEGS1, and EVL), whereas leptin induced progesterone receptor mRNA expression.In conclusion, the current study indicates an interaction of leptin-and adiponectin-signaling pathways in MCF-7 cancer cells whose proliferation is stimulated by leptin and suppressed by adiponectin.

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Expression profiles of MUC1, MUC2, and MUC4 mucins in human neoplasms and their relationship with biological behavior

Cited by 109 publications

References 61 publications

Mucin production determines sensitivity to bortezomib and gemcitabine in pancreatic cancer cells

Mucin production determines sensitivity to bortezomib and gemcitabine in pancreatic cancer cells

Whole-exome characterization of pancreatic neuroendocrine tumor cell lines BON-1 and QGP-1

Involvement of adiponectin and leptin in breast cancer: clinical and in vitro studies

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