Expression of olfactomedin 4 and claudin‐18 in serrated neoplasia of the colorectum: a characteristic pattern is associated with sessile serrated lesion

Sentani, Kazuhiro; Sakamoto, Naoya; Shimamoto, Fumio; Anami, Katsuhiro; Oue, Naohide; Yasui, Wataru

doi:10.1111/his.12099

Cited by 18 publications

(23 citation statements)

References 37 publications

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“…In CLDN18-expressing cases, the pathology of colon cancer is similar to that of gastric cancers, and CLDN18 expression is related to poor survival [74]. CLDN18 expression has also been reported to be associated with serrated adenocarcinoma of the colon [75]. These data indicate that aberrant expression of TJ proteins and of phenotype markers is strongly related to the progression and poor prognosis of cancers.…”

Section: Colon Cancermentioning

confidence: 91%

Gastrointestinal mucosal barrier function and diseases

2016

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The gastrointestinal mucosal barrier plays an essential role in the separation of the inside of the body from the outside environment. Tight junctions (TJs) are the most important component for construction of a constitutive barrier of epithelial cells, and they regulate the permeability of the barrier by tightly sealing the cell-cell junctions. TJ proteins are represented by claudins, occludin, junctional adhesion molecules, and scaffold protein zonula occludens. Among these TJ proteins, claudins are the major components of TJs and are responsible for the barrier and the polarity of the epithelial cells. Gastrointestinal diseases including reflux esophagitis, inflammatory bowel disease, functional gastrointestinal disorders, and cancers may be regulated by these molecules, and disruption of their functions leads to chronic inflammatory conditions and chronic or progressive disease. Therefore, regulation of the barrier function of epithelial cells by regulating the expression and localization of TJ proteins is a potential new target for the treatment of these diseases. Treatment strategies for these diseases might thus be largely altered if symptom generation and/or immune dysfunction could be regulated through improvement of mucosal barrier function. Since TJ proteins may also modify tumor infiltration and metastasis, other important goals include finding a good TJ biomarker of cancer progression and patient prognosis, and developing TJ protein-targeted therapies that can modify patient prognosis. This review summarizes current understanding of gastrointestinal barrier function, TJ protein expression, and the mechanisms underlying epithelial barrier dysregulation in gastrointestinal diseases.

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Section: Colon Cancermentioning

confidence: 91%

Gastrointestinal mucosal barrier function and diseases

2016

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“…It was reported that the activation of Wnt/β‐catenin signaling occurred via distinct mechanisms in both pathways . Furthermore, there are several immunohistochemical markers that can assist in the conventional morphological diagnosis in tumors that develop via the colorectal carcinogenesis pathway, including, but not limited to p53, β‐catenin, claudin‐18, MLH1 and MSH2 . In the present study, we analyzed the significance of SPC18 in pre‐cancerous lesions of both colorectal carcinogenesis pathways.…”

mentioning

confidence: 95%

“…In the search for new therapeutic or diagnostic markers, it is generally accepted that genes expressed at high levels in tumors and at very low levels in normal tissues are ideal diagnostic or therapeutic molecules . We previously reported that Reg IV, olfactomedin 4, claudin‐18 and h‐prune are prognostic makers for CRC . In the present study, we searched for the candidate genes that met these conditions in our comprehensive gene expression libraries, and focused on SEC11A , which encodes the SPC18 protein .…”

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confidence: 99%

Clinicopathological significance of SPC18 in colorectal cancer: SPC18 participates in tumor progression

et al. 2017

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Colorectal cancer (CRC) is one of the leading causes of cancer‐related death worldwide. In order to identify novel prognostic markers or therapeutic targets for CRC, we searched for candidate genes in our comprehensive gene expression libraries, and focused on SEC11A, which encodes the SPC18 protein. SPC18 plays a key role in the endoplasmic reticulum‐Golgi secretory pathway and presumably regulates the secretion of various secretory proteins. An immunohistochemical analysis of SPC18 in 137 CRC tissue samples demonstrated that 79 (58%) CRC cases were positive for SPC18. SPC18‐positive CRC cases were more advanced in terms of N classification (P = 0.0315) and tumor stage (P = 0.0240) than SPC18‐negative CRC cases. Furthermore, the expression of SPC18 was an independent prognostic classifier for CRC patients. The cell growth and invasiveness of SPC18 siRNA‐transfected CRC cell lines was less than that of the negative control siRNA‐transfected cell lines. The levels of phosphorylated epidermal growth factor receptor, Erk and Akt were lower in SPC18 siRNA‐transfected CRC cells than in control cells. The expression of SPC18 was colocalized with β‐catenin nuclear localization and MMP7 at the invasive front. An immunohistochemical analysis of human colorectal polyp specimens revealed a sequential increase in the expression of SPC18 through the conventional adenoma‐carcinoma pathway, while SPC18 was not expressed or was expressed to a lesser extent in serrated pathway‐related tumors. These results suggest that SPC18 is involved in tumor progression, and is an independent prognostic classifier in patients with CRC.

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“…CLDN1 was found to be upregulated in polyps bearing the BRAF V600E somatic mutation, on both the gene expression and protein level . Another study that investigated immunohistochemical detection of CLDN18 in serrated pathway lesions found higher expression of this TJ protein in sessile‐serrated adenomas than in hyperplastic polyps or conventional adenomas . Furthermore, mucin‐5AC expression was reported to be higher in sessile‐serrated adenomas than in normal colon tissue and hyperplastic polyps .…”

Section: Discussionmentioning

confidence: 99%

“…53 Another study that investigated immunohistochemical detection of CLDN18 in serrated pathway lesions found higher expression of this TJ protein in sessile-serrated adenomas than in hyperplastic polyps or conventional adenomas. 54 Furthermore, mucin-5AC expression was reported to be higher in sessile-serrated adenomas than in normal colon tissue and hyperplastic polyps. 55 Mucin "positive" colorectal carcinomas (where staining was observed in more than 25% tumor cells for mucin-2 or >0% for mucins-5AC and -6) were more likely to be CIMP-positive and BRAF V600E-mutated relative to colorectal carcinomas that did not meet the staining threshold.…”

Section: Discussionmentioning

confidence: 99%

Effects of supplemental calcium and vitamin D on tight‐junction proteins and mucin‐12 expression in the normal rectal mucosa of colorectal adenoma patients

Mandle

Jahan

Bostick

et al. 2019

Molecular Carcinogenesis

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The physical gut barrier, comprised of a thick mucus layer and the epithelium, plays an important role in defense against microbes and foreign antigens. Calcium and vitamin D may be involved in maintaining the integrity of the intestinal mucosal barrier, the dysfunction of which may lead to endotoxemia and inflammation, and contribute to colorectal carcinogenesis. We investigated supplemental calcium (1200 mg, daily) and/or vitamin D3 (1000 IU daily) effects on intestinal barrier function‐related biomarkers in a subset of 105 participants from a large colorectal adenoma recurrence chemoprevention clinical trial. We assessed expression of the tight junction proteins claudin‐1 (CLDN1), occludin (OCLD), and mucin‐12 (MUC12) in the normal‐appearing colorectal mucosa using standardized, automated immunohistochemistry and quantitative image analysis. Following 1 year of treatment, in the calcium relative to the no calcium group, the CLDN1, OCLD, and MUC12 expression increased by 14% (P = 0.17), 23% (P = 0.11), and 22% (P = 0.07), respectively. In secondary analyses, the estimated calcium treatment effects were greater among participants with baseline serum 25‐OH‐vitamin D concentrations below the median value of 22.69 ng/mL (CLDN1: 29%, P = 0.04; OCLD: 36%, P = 0.06; MUC12: 35%, P = 0.05). There were no biomarker expression changes in the vitamin D3 alone group; however, modest increases were found in the combined calcium/vitamin D3 group. At baseline, obesity, history of a sessile‐serrated adenoma, colorectal MIB‐1/Ki‐67 expression, and a family history of colorectal cancer were associated with CLDN1, OCLD, and MUC12 expression. Our study supports continued investigation of factors that could affect intestinal mucosal barrier integrity relevant to colorectal carcinogenesis.

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Expression of olfactomedin 4 and claudin‐18 in serrated neoplasia of the colorectum: a characteristic pattern is associated with sessile serrated lesion

Abstract: Reduced expression of olfactomedin 4 and ectopic expression of claudin-18 might be useful markers in the differential diagnosis of serrated polyps.

Cited by 18 publications

References 37 publications

Gastrointestinal mucosal barrier function and diseases

Gastrointestinal mucosal barrier function and diseases

Clinicopathological significance of SPC18 in colorectal cancer: SPC18 participates in tumor progression

Effects of supplemental calcium and vitamin D on tight‐junction proteins and mucin‐12 expression in the normal rectal mucosa of colorectal adenoma patients

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