Different Levels of Sialyl-Tn Antigen Expressed on MUC16 in Patients With Endometriosis and Ovarian Cancer

Akita, Kaoru; Yoshida, Shuhei; Ikehara, Yuzuru; Shirakawa, Sayumi; Toda, Munetoyo; Inoue, Mizue; Kitawaki, Jo; Nakanishi, Hayao; Narimatsu, Hisashi; Nakada, Hiroshi

doi:10.1097/igc.0b013e3182473292

Cited by 46 publications

(41 citation statements)

References 32 publications

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“…STn antigen expression is observed in many epithelial cancers, and its expression correlates with enhanced expression of ST6GalNAc-I [108] and elevated serum levels of STn antigen are associated with poor prognosis [109,110]. Recent studies have shown that for patients with ovarian cancer, evaluating the serum levels of STn in circulating mucins, such as MUC16 (now known to be the CA125 antigen), a mucin produced by ovarian tumors and whose ectodomain is found in blood, may aid in diagnosis, tumor staging, and type [111]. STn expression is also enhanced in patients with ovarian cancer, but not in patients with en-dometriosis, in contrast to expression of the antigen CA125, which is often overexpressed in both conditions [111].…”

Section: Expression Of Tn Antigen In Tumorsmentioning

confidence: 99%

“…Recent studies have shown that for patients with ovarian cancer, evaluating the serum levels of STn in circulating mucins, such as MUC16 (now known to be the CA125 antigen), a mucin produced by ovarian tumors and whose ectodomain is found in blood, may aid in diagnosis, tumor staging, and type [111]. STn expression is also enhanced in patients with ovarian cancer, but not in patients with en-dometriosis, in contrast to expression of the antigen CA125, which is often overexpressed in both conditions [111]. Expression of STn antigen is associated with poor prognosis, and in the case of gastrointestinal adenocarcinomas its expression is dependent on the aberrant expression of ST6GalNAc-I [112].…”

Section: Expression Of Tn Antigen In Tumorsmentioning

confidence: 99%

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The Cosmc connection to the Tn antigen in cancer

Aryal

Kudelka

et al. 2014

CBM

122

125

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The Tn antigen is a tumor-associated carbohydrate antigen that is not normally expressed in peripheral tissues or blood cells. Expression of this antigen, which is found in a majority of human carcinomas of all types, arises from a blockage in the normal O-glycosylation pathway in which glycans are extended from the common precursor GalNAcα1-O-Ser/Thr (Tn antigen). This precursor is generated in the Golgi apparatus on newly synthesized glycoproteins by a family of polypeptide αN-acetylgalactosaminyltransferases (ppGalNAcTs) and then extended to the common core 1 O-glycan Galβ1-3GalNAcα1-O-Ser/Thr (T antigen) by a single enzyme termed the T-synthase (core 1 β3-galactosyltransferase or C1GalT). Formation of the active form of the T-synthase requires a unique molecular chaperone termed Cosmc, encoded by Cosmc on the X-chromosome (Xq24 in humans, Xc3 in mice). Cosmc resides in the endoplasmic reticulum (ER) and prevents misfolding, aggregation, and proteasome-dependent degradation of newly synthesized T-synthase. Loss of expression of active T-synthase or Cosmc can lead to expression of the Tn antigen, along with its sialylated version Sialyl Tn antigen as observed in several cancers. Both genetic and epigenetic pathways, in addition to potential metabolic regulation, can result in abnormal expression of the Tn antigen. Engineered expression of the Tn antigen by disruption of either C1GalT (T-syn) or Cosmc in mice is associated with a tremendous range of pathologies and engineered expression of the Tn antigen in mouse embryos leads to embryonic death. Studies indicate that many membrane glycoproteins expressing the Tn antigen and/or truncated O-glycans may be dysfunctional, due to degradation and/or misfolding. Thus, expression of normal O-glycans is associated with health and homeostasis whereas truncation of O-glycans, e.g. the Tn and/or Sialyl Tn antigens is associated with cancer and other pathologies.

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Section: Expression Of Tn Antigen In Tumorsmentioning

confidence: 99%

Section: Expression Of Tn Antigen In Tumorsmentioning

confidence: 99%

The Cosmc connection to the Tn antigen in cancer

Aryal

Kudelka

et al. 2014

CBM

122

125

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“…Although the association between ST6GalNAc-I and the expression of sTn is still not fully clear, sTn antigen is highly expressed in most gastric [22], colorectal [23], ovarian [24], breast [25] and pancreatic carcinomas [26] whereas no expression is observed in the respective normal tissues. The positive correlation of sTn with carcinoma aggressiveness and poor prognosis has motivated the research on sialyl-Tn role in cancer cell biology.…”

Section: Introductionmentioning

confidence: 99%

O-glycan sialylation alters galectin-3 subcellular localization and decreases chemotherapy sensitivity in gastric cancer

et al. 2016

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ST6GalNAc-I, the sialyltransferase responsible for sialyl-Tn (sTn) synthesis, has been previously reported to be positively associated with cancer aggressiveness. Here we describe a novel sTn-dependent mechanism for chemotherapeutic resistance. We show that sTn protects cancer cells against chemotherapeutic-induced cell death by decreasing the interaction of cell surface glycan receptors with galectin-3 and increasing its intracellular accumulation. Moreover, exogenously added galectin-3 potentiated the chemotherapeutics-induced cytotoxicity in sTn non-expressing cells, while sTn overexpressing cells were protected. We also found that the expression of sTn was associated with a reduction in galectin-3-binding sites in human gastric samples tumors. ST6GalNAc-I knockdown restored galectin-3-binding sites on the cell surface and chemotherapeutics sensibility. Our results clearly demonstrate that an interruption of O-glycans extension caused by ST6GalNAc-I enzymatic activity leads to tumor cells resistance to chemotherapeutic drugs, highlighting the need for the development of novel strategies to target galectin-3 and/or ST6GalNAc-I.

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“…4 It was recently found that the glycosylation of CA125 in patients with EOC is different from that in healthy subjects and patients with benign ovarian neoplasms, providing an attractive target for qualitative evaluation of this mucin. [5][6][7] However, the biochemical tools for specifically detecting such altered glycosylation are limited.…”

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confidence: 99%

Difference in mesothelin‐binding ability of serum CA125 between patients with endometriosis and epithelial ovarian cancer

Sasaki

Akita

Ito

et al. 2014

Intl Journal of Cancer

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The epithelial ovarian carcinoma (EOC) is an aggressive malignant tumor, and is currently the leading cause of gynecologic cancer death. CA125 is the most commonly used serum marker for EOC, but shows a high-false-positive rate for several benign diseases such as endometriosis. The purpose of our study is therefore to identify a useful biochemical tool for detecting qualitative differences between CA125 from patients with endometriosis and EOC, and to facilitate differential diagnosis of these diseases. In our study, using two different CA125-binding molecules, i.e., recombinant mesothelin and an anti-CA125 monoclonal antibody, a novel sandwich ELISA for determining the serum levels of CA125 with mesothelin-binding ability (CA125 meso ) was developed, and tested for patients with endometriosis (n 5 59) and EOC (n 5 36). We found that both the serum CA125 meso level and the ratio of the serum CA125 meso to CA125 levels (CA125 meso /CA125) were significantly higher in patients with EOC than in patients with endometriosis (p < 0.00005 and p < 0.000001, respectively). Furthermore, receiver operating characteristic analysis showed that the CA125 meso assay was superior to the conventional antibody-based CA125 assay in discriminating endometriosis from EOC. Thus, mesothelin-binding ability may be a useful indicator for qualitatively evaluating CA125 in patients with endometriosis and EOC.

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Different Levels of Sialyl-Tn Antigen Expressed on MUC16 in Patients With Endometriosis and Ovarian Cancer

Abstract: Estimation of the sTn/MUC16 level may be useful for discriminating endometriosis from ovarian cancer and for evaluating the clinical stage, cytological grade, and histological type of ovarian cancer.

Cited by 46 publications

References 32 publications

The Cosmc connection to the Tn antigen in cancer

The Cosmc connection to the Tn antigen in cancer

O-glycan sialylation alters galectin-3 subcellular localization and decreases chemotherapy sensitivity in gastric cancer

Difference in mesothelin‐binding ability of serum CA125 between patients with endometriosis and epithelial ovarian cancer

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