Association and diagnostic value of serum SPINK4 in colorectal cancer

Xie, Min; Li, Kezhi; Li, Jilin; Lu, Dongcheng; Hu, Bang-li

doi:10.7717/peerj.6679

Cited by 8 publications

(7 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Due to the limited sample size of adenoma cases in the present study, whether SPINK4 can be used as a predictor of CRC formation requires further study. Interestingly, the serum SPINK4 level was increased in patients with CRC compared with that in healthy controls in previous research [10]. Since proteins are secreted by various cells as a response to various stimuli, determining whether serum SPINK4 is directly derived from the tumor needs further research.…”

Section: Discussionmentioning

confidence: 91%

“…With regard to the value of serum SPINK4 for predicting survival, Xie et al [10] did not find that serum SPINK4 was associated with OS or DFS in CRC patients. The short follow-up time (less than 10 months in half of the patients) as well as the small sample size in that study might partially explain the negative result.…”

Section: Discussionmentioning

confidence: 99%

“…SPINK4 is abundantly expressed in human goblet cells but was also reported to be formed, stored, and secreted from monocytes and might function as a gastrointestinal peptide [9]. A previous study found that serum SPINK4 levels were increased in CRC and had high diagnostic value but were not associated with the survival of CRC patients [10]. The expression status of SPINK4 in tissue samples and its clinical significance in CRC is largely unknown.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Downregulated SPINK4 is associated with poor survival in colorectal cancer

Wang

Ghareeb

et al. 2019

BMC Cancer

View full text Add to dashboard Cite

BackgroundSPINK4 is known as a gastrointestinal peptide in the gastrointestinal tract and is abundantly expressed in human goblet cells. The clinical significance of SPINK4 in colorectal cancer (CRC) is largely unknown.MethodsWe retrieved the expression data of 1168 CRC patients from 3 Gene Expression Omnibus (GEO) datasets (GSE24551, GSE39582, GSE32323) and The Cancer Genome Atlas (TCGA) to compare the expression level of SPINK4 between CRC tissues and normal colorectal tissues and to evaluate its value in predicting the survival of CRC patients. At the protein level, these results were further confirmed by data mining in the Human Protein Atlas and by immunohistochemical staining of samples from 81 CRC cases in our own center.ResultsSPINK4 expression was downregulated in CRC compared with that in normal tissues, and decreased SPINK4 expression at both the mRNA and protein levels was associated with poor prognosis in CRC patients from all 3 GEO datasets, the TCGA database and our cohort. Additionally, lower SPINK4 expression was significantly related to higher TNM stage. Moreover, in multivariate regression, SPINK4 was confirmed as an independent indicator of poor survival in CRC patients in all databases and in our own cohort.ConclusionsWe concluded that reduced expression of SPINK4 relates to poor survival in CRC, functioning as a novel indicator.

show abstract

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Downregulated SPINK4 is associated with poor survival in colorectal cancer

Wang

Ghareeb

et al. 2019

BMC Cancer

View full text Add to dashboard Cite

show abstract

“…As a protease inhibitor, SPINK4 is believed to participate in the defense against the proteolytic degradation of mucosal and epithelial tissues. Interestingly, it has been suggested that the serum SPINK4 level is increased in colorectal cancer patients and has high diagnostic utility [ 9 ], whereas the expression of SPINK4 has been reported to be reduced in colorectal cancer tumor specimens and associated with poor survival [ 10 ]. However, the expression of SPINK4 in tumor tissues from patients receiving neoadjuvant CCRT, as well as its practical importance—especially for rectal cancer—are largely unrevealed.…”

Section: Introductionmentioning

confidence: 99%

High SPINK4 Expression Predicts Poor Outcomes among Rectal Cancer Patients Receiving CCRT

et al. 2021

View full text Add to dashboard Cite

Background: Patients with rectal cancer can prospectively be favored for neoadjuvant concurrent chemoradiotherapy (CCRT) to downstage before a radical proctectomy, but the risk stratification and clinical outcomes remain disappointing. Methods: From a published rectal cancer transcriptome dataset (GSE35452), we highlighted extracellular matrix (ECM)-linked genes and identified the serine protease inhibitor Kazal-type 4 (SPINK4) gene as the most relevant among the top 10 differentially expressed genes associated with CCRT resistance. We accumulated the cases of 172 rectal cancer patients who received neoadjuvant CCRT followed by surgery and collected tumor specimens for the evaluation of the expression of SPINK4 using immunohistochemistry. Results: The results revealed that high SPINK4 immunoexpression was significantly related to advanced pre-CCRT and post-CCRT tumor status (both p < 0.001), post-CCRT lymph node metastasis (p = 0.001), more vascular and perineurial invasion (p = 0.015 and p = 0.023), and a lower degree of tumor regression (p = 0.001). In univariate analyses, high SPINK4 immunoexpression was remarkably correlated with worse disease-specific survival (DSS) (p < 0.0001), local recurrence-free survival (LRFS) (p = 0.0017), and metastasis-free survival (MeFS) (p < 0.0001). Furthermore, in multivariate analyses, high SPINK4 immunoexpression remained independently prognostic of inferior DSS and MeFS (p = 0.004 and p = 0.002). Conclusion: These results imply that high SPINK4 expression is associated with advanced clinicopathological features and a poor therapeutic response among rectal cancer patients undergoing CCRT, thus validating the prospective prognostic value of SPINK4 for those patients.

show abstract

“… 20 These transcripts include SPEM-associated transcripts such as Muc6 , Agr2 , and Tff2 ; the metaplasia-associated transcript Gkn3 ; the long noncoding RNA transcript Xist , which has been implicated in gastric cancer cell biology by promoting proliferation and progression; and Spink4 , a serine peptidase inhibitor associated with malignant colorectal cancer. 46 , 47 Analysis of the transcriptional differences between TxA23 and TxA23× Il4ra -/- mucous neck cells showed a total of 41 differentially expressed genes with a greater than 2-fold change ( Figure 7 D ). SPEM-associated transcripts Gkn3 , Tff2 , Muc6 , Spink4 , and Xist were up-regulated significantly in TxA23 neck cells relative to that of TxA23× Il4ra -/- , while expression of Agr2 was similar between the 2 libraries ( Figure 7 F ).…”

Section: Resultsmentioning

confidence: 99%

IL13 Acts Directly on Gastric Epithelial Cells to Promote Metaplasia Development During Chronic Gastritis

Noto

Hoft

Bockerstett

et al. 2022

Cellular and Molecular Gastroenterology and Hepatology

View full text Add to dashboard Cite

Interleukin 13 (IL13) is secreted by multiple subsets of immune cells and acts directly on the gastric epithelium to promote neck cell expansion and metaplasia. Mice with autoimmune gastritis lacking the IL13 receptor do not develop neck cell expansion or metaplasia, and neutralization of IL13 inhibits and reverses disease development during chronic gastritis. BACKGROUND & AIMS:It is well established that chronic inflammation promotes gastric cancer-associated metaplasia, but little is known regarding the mechanisms by which immune cells and cytokines regulate metaplastic cellular changes. The goals of this study were to identify interleukin 13 (IL13)-producing immune cells, determine the gastric epithelial cell response(s) to IL13, and establish the role(s) of IL13 in metaplasia development. METHODS:Experiments used an established mouse model of autoimmune gastritis (TxA23), TxA23xIl4ra Q9 -/mice, which develop gastritis but do not express the IL4/IL13-receptor subunit IL4Ra, and TxA23xIL13-YFP Q10 mice, which express yellow fluorescent protein in IL13-producing cells. Flow cytometry was used to measure IL13 secretion and identify IL13producing immune cells. Mouse and human gastric organoids were cultured with IL13 to determine epithelial cell response(s) to IL13. Single-cell RNA sequencing was performed on gastric epithelial cells from healthy and inflamed mouse stomachs. Mice with gastritis were administered IL13neutralizing antibodies and stomachs were analyzed by histopathology and immunofluorescence. RESULTS:We identified 6 unique subsets of IL13-producing immune cells in the inflamed stomach. Organoid cultures showed that IL13 acts directly on gastric epithelium to induce a metaplastic phenotype. IL4Ra-deficient mice did not progress to metaplasia. Single-cell RNA sequencing determined that gastric epithelial cells from IL4Ra-deficient mice up-regulated inflammatory genes but failed to up-regulate metaplasia-associated transcripts. Neutralization of IL13 significantly reduced and reversed metaplasia development in mice with gastritis.CONCLUSIONS: IL13 is made by a variety of immune cell subsets during chronic gastritis and promotes gastric cancer-associated metaplastic epithelial cell changes. Neutralization of IL13 reduces metaplasia severity during chronic gastritis.

show abstract

Association and diagnostic value of serum SPINK4 in colorectal cancer

Cited by 8 publications

References 30 publications

Downregulated SPINK4 is associated with poor survival in colorectal cancer

Downregulated SPINK4 is associated with poor survival in colorectal cancer

High SPINK4 Expression Predicts Poor Outcomes among Rectal Cancer Patients Receiving CCRT

IL13 Acts Directly on Gastric Epithelial Cells to Promote Metaplasia Development During Chronic Gastritis

Contact Info

Product

Resources

About