Digital PCR identifies changes in CDH1 (E-cadherin) transcription pattern in intestinal-type gastric cancer

Raefa Abou Khouzam, Chiara Molinari, Samanta Salvi, Monica Marabelli, Valeria Molinaro, Donata Orioli, Luca Saragoni, Paolo Morgagni, Daniele Calistri, Guglielmina Nadia Ranzani

Research output: Contribution to journalArticle

Abstract

E-cadherin is a cell-cell adhesion protein encoded by CDH1 tumor-suppressor gene. CDH1 inactivating mutations, leading to loss of protein expression, are common in gastric cancer of the diffuse histotype, while alternative mechanisms modulating E-cadherin expression characterize the more common intestinal histotype. These mechanisms are still poorly understood. CDH1 intron 2 has recently emerged as a cis-modulator of E-cadherin expression, encoding non-canonical transcripts. One in particular, CDH1a, proved to be expressed in gastric cancer cell lines, while being absent in the normal stomach. For the first time, we evaluated by digital PCR the expression of CDH1 and CDH1a transcripts in cancer and normal tissue samples from 32 patients with intestinal-type gastric cancer. We found a significant decrease in CDH1 expression in tumors compared to normal counterparts (P = 0.001), which was especially evident in 76% of cases. CDH1a was detected at extremely low levels in 47% of tumors, but not in normal mucosa. A trend was observed of having less CDH1 in tumors expressing CDH1atranscript. The majority of tumors with both a decrease in CDH1 and presence of CDH1a also showed a decrease in miR-101 expression levels. On the whole, the decrease of CDH1 transcript, corresponding to the canonical protein, and the presence of CDH1a, corresponding to an alternative isoform, are likely to perturb E-cadherin-mediated signaling and cell-cell adhesion, thus contributing to intestinal-type gastric carcinogenesis.

Original languageEnglish
JournalOncotarget
DOIs
Publication statusE-pub ahead of print - Nov 16 2016

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Intestinal Neoplasms
Cadherins
Stomach Neoplasms
Polymerase Chain Reaction
Neoplasms
Cell Adhesion
Stomach
Proteins
Tumor Suppressor Genes
Introns
Protein Isoforms
Carcinogenesis
Mucous Membrane
Cell Line
Mutation

Keywords

  • Journal Article

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Digital PCR identifies changes in CDH1 (E-cadherin) transcription pattern in intestinal-type gastric cancer. / Abou Khouzam, Raefa; Molinari, Chiara; Salvi, Samanta; Marabelli, Monica; Molinaro, Valeria; Orioli, Donata; Saragoni, Luca; Morgagni, Paolo; Calistri, Daniele; Ranzani, Guglielmina Nadia.

In: Oncotarget, 16.11.2016.

Research output: Contribution to journalArticle

Abou Khouzam, Raefa ; Molinari, Chiara ; Salvi, Samanta ; Marabelli, Monica ; Molinaro, Valeria ; Orioli, Donata ; Saragoni, Luca ; Morgagni, Paolo ; Calistri, Daniele ; Ranzani, Guglielmina Nadia. / Digital PCR identifies changes in CDH1 (E-cadherin) transcription pattern in intestinal-type gastric cancer. In: Oncotarget. 2016.
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abstract = "E-cadherin is a cell-cell adhesion protein encoded by CDH1 tumor-suppressor gene. CDH1 inactivating mutations, leading to loss of protein expression, are common in gastric cancer of the diffuse histotype, while alternative mechanisms modulating E-cadherin expression characterize the more common intestinal histotype. These mechanisms are still poorly understood. CDH1 intron 2 has recently emerged as a cis-modulator of E-cadherin expression, encoding non-canonical transcripts. One in particular, CDH1a, proved to be expressed in gastric cancer cell lines, while being absent in the normal stomach. For the first time, we evaluated by digital PCR the expression of CDH1 and CDH1a transcripts in cancer and normal tissue samples from 32 patients with intestinal-type gastric cancer. We found a significant decrease in CDH1 expression in tumors compared to normal counterparts (P = 0.001), which was especially evident in 76{\%} of cases. CDH1a was detected at extremely low levels in 47{\%} of tumors, but not in normal mucosa. A trend was observed of having less CDH1 in tumors expressing CDH1atranscript. The majority of tumors with both a decrease in CDH1 and presence of CDH1a also showed a decrease in miR-101 expression levels. On the whole, the decrease of CDH1 transcript, corresponding to the canonical protein, and the presence of CDH1a, corresponding to an alternative isoform, are likely to perturb E-cadherin-mediated signaling and cell-cell adhesion, thus contributing to intestinal-type gastric carcinogenesis.",
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AU - Salvi, Samanta

AU - Marabelli, Monica

AU - Molinaro, Valeria

AU - Orioli, Donata

AU - Saragoni, Luca

AU - Morgagni, Paolo

AU - Calistri, Daniele

AU - Ranzani, Guglielmina Nadia

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AB - E-cadherin is a cell-cell adhesion protein encoded by CDH1 tumor-suppressor gene. CDH1 inactivating mutations, leading to loss of protein expression, are common in gastric cancer of the diffuse histotype, while alternative mechanisms modulating E-cadherin expression characterize the more common intestinal histotype. These mechanisms are still poorly understood. CDH1 intron 2 has recently emerged as a cis-modulator of E-cadherin expression, encoding non-canonical transcripts. One in particular, CDH1a, proved to be expressed in gastric cancer cell lines, while being absent in the normal stomach. For the first time, we evaluated by digital PCR the expression of CDH1 and CDH1a transcripts in cancer and normal tissue samples from 32 patients with intestinal-type gastric cancer. We found a significant decrease in CDH1 expression in tumors compared to normal counterparts (P = 0.001), which was especially evident in 76% of cases. CDH1a was detected at extremely low levels in 47% of tumors, but not in normal mucosa. A trend was observed of having less CDH1 in tumors expressing CDH1atranscript. The majority of tumors with both a decrease in CDH1 and presence of CDH1a also showed a decrease in miR-101 expression levels. On the whole, the decrease of CDH1 transcript, corresponding to the canonical protein, and the presence of CDH1a, corresponding to an alternative isoform, are likely to perturb E-cadherin-mediated signaling and cell-cell adhesion, thus contributing to intestinal-type gastric carcinogenesis.

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