Testican-1-mediated epithelial–mesenchymal transition signaling confers acquired resistance to lapatinib in HER2-positive gastric cancer

Hp, Kim; Sw, Han; Song, Shlee; Eg, Jeong; Lee, MY; Hwang, Dong Soo; Im, Sungbin; Bang, Y-J.; Ty, Kim

doi:10.1038/onc.2013.285

Cited by 95 publications

(90 citation statements)

References 39 publications

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“…In the case of gastric cancer, the involvement of STAT3 in the resistance to treatment has been reported in the literature [52][53][54][55][56]. Furthermore, this resistance is associated with the activation of Stat3 and EMT [19,57]. The molecular interaction of STAT3 and Snail, ZIP6, and also the other transcription factors suggests that it is part of a core that controls EMT in normal and pathological conditions [58,59].…”

Section: Discussionmentioning

confidence: 99%

The Lauren Classification Highlights the Role of Epithelialto- Mesenchymal Transition in Gastric Carcinogenesis: an Immunohistochemistry Study of the STAT3 and Adhesion Molecules Expression

Şuşman¹,

Barnoud²,

Bibeau³

et al. 2015

JGLD

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Background & Aims: Despite some recent advances, gastric cancer remains an important cause of death at world level. This indicates an absence of therapeutic options, stemming from the limited understanding of the molecular mechanisms involved in carcinogenesis. Nearly fifty years ago Lauren classified gastric cancers, according to the morphological aspect, as intestinal or diffuse. The phenotype of the cells indicates the presence of different molecular mechanisms, which can be approached in the light of recent data and identified with the help of current techniques. The best described are the germline/somatic mutations or the hypermethylations of the E-cadherin 1 CDH1 gene promotor.Methods. We analyzed 195 gastric tumors,120 intestinal and 75 diffuse type, using immunohistochemistry (tissue microarray TMA method) for pStat3Tyr705, E-cadherin, α-catenin and β-catenin; 985 spots of gastric tumors, distributed on 4 TMA blocks were analyzed. For pStat3Tyr705 we took the nuclear staining into account and for the adhesion molecules, membrane staining.Results. In our study, in the diffuse type gastric cancer, pStat3Tyr705 nuclear expression was statistically significantly increased (p=0.003). Also we observed a decreased expression of the adhesion molecules in the same type of gastric cancer (E-cadherin p<0.0001, α-catenin p<0.0001, β-catenin p<0.0001), suggesting that epithelial-to-mesenchymal transition (EMT) may be involved not only in gastric carcinogenesis, but also in resistance to treatment.Conclusion. The Stat3 role has been recently highlighted in carcinogenesis of the diffuse type of gastric cancer. We found that the morphological features of the diffuse type also suggest the involvement of EMT in this type of gastric cancer. Therefore, targeting the key molecules involved in this process may interfere with EMT process in the diffuse type of gastric cancer.

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Section: Discussionmentioning

confidence: 99%

The Lauren Classification Highlights the Role of Epithelialto- Mesenchymal Transition in Gastric Carcinogenesis: an Immunohistochemistry Study of the STAT3 and Adhesion Molecules Expression

Şuşman¹,

Barnoud²,

Bibeau³

et al. 2015

JGLD

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“…Characteristics of the mesenchymal phenotype include the expression of vimentin, α-SMA, fibronectin and N-cadherin. These EMT-related events were observed not only in CRC, but also in various types of human cancers [11,15], including esophageal cell carcinoma, and gastric, ovary and breast cancer [16,17,18,19]. …”

Section: Discussionmentioning

confidence: 99%

Loss of E-Cadherin Expression Is Associated with a Poor Prognosis in Stage III Colorectal Cancer

Yun

Kim²,

Hong³

et al. 2014

Oncology

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Purpose: The epithelial-mesenchymal transition (EMT) is known to be associated with tumor progression, invasion and metastasis in colorectal cancer (CRC). Materials and Methods: Tissue samples obtained from 409 patients with stage III CRC treated from 2006 to 2007 were examined by immunohistochemistry to reveal the expression levels of E-cadherin, fibronectin, vimentin and α-smooth muscle actin (SMA). Results: Among the 409 patients, 402 cases (98.3%) showed positive E-cadherin expression. Positive E-cadherin expression was associated with well or moderately differentiated cell types and a stable microsatellite status. In multivariate analysis, a preoperative carcinoembryonic antigen level >5 ng/ml (p = 0.021), advanced N stage (p = 0.017), positive vascular invasion (p = 0.048), positive perineural invasion (p = 0.002) and negative E-cadherin expression (p = 0.002, relative risk = 5.098, 95% CI = 1.801-14.430) were poor prognostic factors affecting disease-free survival. The declining E-cadherin expression was associated with a poor outcome in terms of overall survival in univariate (p = 0.016) but not in multivariate analyses (p = 0.303, relative risk = 1.984, 95% CI = 0.539-7.296). Fibronectin, vimentin and α-SMA were of no prognostic value in this study. Conclusion: The expression pattern of EMT markers in stage III CRC suggests that declining E-cadherin expression is a possible immunohistochemical predictor of patient prognosis.

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“…SPARC proteins are involved in cell proliferation, adhesion, migration, and apoptosis in various tumors [28]. An altered expression with potential implication in tumor development of SPOCK1 has been shown in gastrointestinal neuroendocrine tumors and gastric and hepatocellular carcinomas [29][30][31]. Although upregulation of SPOCK1 was recently reported in prostatic adenocarcinomas [32], the function of SPOCK1 in prostate cancer has not been clearly elucidated.…”

Section: Introductionmentioning

confidence: 98%

Plakophilin 1-deficient cells upregulate SPOCK1: implications for prostate cancer progression

et al. 2015

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Plakophilin (PKP) 1 is frequently downregulated in prostate cancer and therefore may play a tumor-suppressive role. In the present study, we stably knocked down PKP1 in the non-neoplastic, prostatic BPH-1 cell line. In the PKP1-deficient cells, the expression of keratin 14 was lost, and the apoptosis rate was significantly reduced indicating that the cells acquired new biological capabilities. Moreover, we analyzed the gene expression profile of the PKP1-deficient BPH-1 cells. Among the genes that were significantly altered upon PKP1 knockdown, we noticed several extracellular matrix (ECM)-related genes and identified sparc/osteonectin, cwcv, and kazal-like domains proteoglycan 1 (SPOCK1/testican-1) as a gene of interest. SPOCK1 is a component of the ECM and belongs to a matricellular protein family named secreted protein, acidic, cysteine-rich (SPARC). The role of SPOCK1 in prostate cancer has not been clearly elucidated. We analyzed SPOCK1 mRNA expression levels in different cancer databases and characterized its expression in 136 prostatic adenocarcinomas by immunohistochemistry and western blot. SPOCK1 revealed a cytoplasmic localization in the glandular epithelium of the prostate and showed a significant upregulation of mRNA and protein in prostate tumor samples. Our findings support the hypothesis that PKP1 may have a tumor-suppressive function and suggest an important role of SPOCK1 in prostate tumor progression. Collectively, altered expression of PKP1 and SPOCK1 appears to be a frequent and critical event in prostate cancer.

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Testican-1-mediated epithelial–mesenchymal transition signaling confers acquired resistance to lapatinib in HER2-positive gastric cancer

Cited by 95 publications

References 39 publications

The Lauren Classification Highlights the Role of Epithelialto- Mesenchymal Transition in Gastric Carcinogenesis: an Immunohistochemistry Study of the STAT3 and Adhesion Molecules Expression

The Lauren Classification Highlights the Role of Epithelialto- Mesenchymal Transition in Gastric Carcinogenesis: an Immunohistochemistry Study of the STAT3 and Adhesion Molecules Expression

Loss of E-Cadherin Expression Is Associated with a Poor Prognosis in Stage III Colorectal Cancer

Plakophilin 1-deficient cells upregulate SPOCK1: implications for prostate cancer progression

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