Significance of E-cadherin and CD44 expression in patients with unresectable metastatic colorectal cancer

Iseki, Yasuhito; Shibutani, Masatsune; Maeda, Kiyoshi; Nagahara, Hisashi; Ikeya, Takashi; Hirakawa, Kosei

doi:10.3892/ol.2017.6269

Cited by 23 publications

(23 citation statements)

References 36 publications

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“…Epithelial-mesenchymal transition (EMT) contributes to the invasion and migration of cRc (33). E-cadherin and N-cadherin are important in EMT of cRc (34,35). The results of the current study demonstrate that E-cadherin was upregulated after ANXA9 inhibition, whereas no obvious variation was verified in N-cadherin.…”

Section: Discussionmentioning

confidence: 56%

Annexin A9 promotes invasion and metastasis of colorectal cancer and predicts poor prognosis

Bian

Gào

et al. 2018

Int J Mol Med

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Annexin A9 (ANXA9), a member of annexin family, has been reported be associated with colorectal cancer (CRC) carcinogenesis. However, the clinical significance of ANXA9 in CRC, particularly its correlation to invasion and metastasis remains ambiguous. The aim of the present study was to investigate the significance of ANXA9 in CRC and understand the molecular mechanism of ANXA9 in CRC invasion and metastasis. Expression levels of the ANXA9 protein in CRC tissues were detected using immunohistochemistry (IHC), and the clinical and prognostic value of ANXA9 was investigated. ANXA9‑siRNA was utilized to investigate the effect and molecular mechanism of ANXA9 in HCT116 cells. The IHC result demonstrated that the positivity rate of the ANXA9 protein in CRC tissue was significantly higher than that in adjacent mucosa (P<0.05), which was consistent with the western blot results. ANXA9 protein expression levels are associated with invasion depth and lymphatic metastasis. Furthermore, patients with ANXA9‑positive expression demonstrated a poor prognosis and ANXA9 was an independent risk factor for survival (P<0.05). After inhibiting ANXA9 in HCT116 cells, the activity and metastatic and invasion capacity of cells decreased significantly, and expression levels of ADAM metallopeptidase domain 17 and matrix metallopeptidase 9 were significantly downregulated, while the expression levels of tissue inhibitors of metalloproteinases‑1 and E‑cadherin were upregulated (P<0.05). Thus, positive ANXA9 expression may present as a novel marker for predicting poor prognosis in CRC patients, and ANXA9 may promote the invasion and metastasis of CRC by regulating invasion and metastasis‑associated genes.

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Section: Discussionmentioning

confidence: 56%

Annexin A9 promotes invasion and metastasis of colorectal cancer and predicts poor prognosis

Bian

Gào

et al. 2018

Int J Mol Med

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“…81 Combined assessment of E-cadherin and CD44 in colorectal cancer has been shown to have a higher prognostic value than isolated evaluation of single markers. 29,82 The pathways of EMT induction and stemness differ by MSI status. Twist1 induced EMT and CD44 via AKT/GSK-3beta/beta-catenin and AKT/NF-kappaB pathways in MSS cells, while only the beta-catenin pathway was activated in MSI colorectal cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…28 A combined low expression of E-cadherin and CD44 is associated with decreased overall survival in patients with metastatic colorectal cancer. 29 Given these prognostic trends, associations between the listed factors might be hypothesized. However, few studies have tried to assess directly the mutual relationships between inflammation, EMT, stem cell differentiation and the expression of MMR proteins in the same cohort of colorectal cancer cases.…”

Section: Introductionmentioning

confidence: 99%

<p>The Association Between Inflammation, Epithelial Mesenchymal Transition and Stemness in Colorectal Carcinoma</p>

Briede¹,

Štrumfa²,

Vanags³

et al. 2020

JIR

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Background: Inflammation plays an important albeit dual role in carcinogenesis. Survival studies have highlighted the prognostic significance of peritumorous inflammation. Currently, the theoretical background allows inflammation, epithelial mesenchymal transition (EMT) and the closely associated stem cell differentiation in colorectal carcinoma (CRC) to be linked. However, there is scarce direct morphological evidence. Purpose and methods: The aim of our study was to investigate the role of inflammation in cancer growth and invasion by analyzing the association between inflammation and known morphological prognostic features of colorectal cancer, EMT, stemness and mismatch repair (MMR) protein expression. The study was designed as a retrospective morphological and immunohistochemical assessment of 553 consecutive cases of surgically treated primary CRC. Results: There were statistically significant associations between high-grade inflammation and lower pT (p = 0.002), absence of lymph node metastases (p < 0.001) and less frequent lymphatic (p = 0.003), venous (p = 0.017), arterial (p = 0.012), perineural (p = 0.001) and intraneural (p = 0.01) invasion. In contrast, Crohn's like reaction (CLR) by density of lymphoid follicles in the invasive front lacked significant differences in regard to pT, pN, tumor invasion into surrounding structures (blood or lymphatic vessels, nerves), grade or necrosis (all p > 0.05). The expression of E-cadherin, CD44 and MMR proteins yielded no statistically significant associations with peritumorous inflammation by Klintrup-Mäkinen score or the density of lymphoid follicles. Nevertheless, E-cadherin levels were significantly associated with the density of eosinophils (p = 0.007). Conclusion: High-grade peritumorous inflammation is associated with beneficial morphologic CRC features, including less frequent manifestations of invasion, and is not secondary to tissue damage and necrosis. CLR is not associated with cancer spread by pTN; this finding indirectly suggests an independent role of CLR in carcinogenesis. Further, inflammation by Klintrup-Mäkinen grade and CLR is not dependent on epithelial-mesenchymal transition and stem cell differentiation. Our study highlights the complex associations between inflammation, tumor morphology, EMT, stemness and MMR protein expression in human CRC tissues.

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“…The destruction of E-cadherin is thought to be one of the first steps in metastasis, playing critical roles in tumor metastasis [21,[31][32][33]. Recent reports have shown that a decrease in E-cadherin is strongly associated with metastasis and poor clinical prognosis and suggested that targeting E-cadherin could be a promising therapeutic approach for metastatic CRC [34]. In this study, we showed that knockdown of DAXX can significantly decrease E-cadherin both at the transcriptional level and the translational level.…”

Section: Discussionmentioning

confidence: 99%

Death Domain-Associated Protein Promotes Colon Cancer Metastasis through Direct Interaction with ZEB1

Liu¹,

Guo

Zhu³

et al. 2020

J. Cancer

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Background: Death domain-associated protein (DAXX) is a tumor suppressor and its loss has been found in a variety of cancer types. Dysregulation of DAXX is strongly correlated with cancer metastasis. However, the role and functions of DAXX in colorectal cancer (CRC) metastasis are not fully understood. Methods: We validated the mRNA and protein expression of DAXX in CRC specimens and CRC cell lines using real-time reverse transcription-PCR and Western blot, respectively. The overexpression plasmids of ZEB1 and E-cadherin and the siRNAs for DAXX and ZEB1 knockdown were constructed to study the impact of these factors on cells. Wound-healing assay and Transwell assay were performed to examine the cell motility and cell migration and invasion abilities, respectively. Luciferase assay was performed to assess the E-cadherin promoter activity. Immunoprecipitation assay was performed to investigate the interaction between proteins. The rescue experiment was carried out to verify whether the effect of DAXX on E-cadherin expression is depended on ZEB1. Results: DAXX expression was lower in liver metastases than in primary colon cancer tissues. Our results demonstrated that DAXX directly interacted with ZEB1 and suppressed its inhibitory effect on promoter activity of E-cadherin through a ZEB1-dependent manner, and thus suppresses the cell motility, migration, and invasion of CRC cell lines. Conclusion: In sum, these findings supported that the loss of DAXX is associated with cancer cell metastases in CRC. ZEB1-mediated transcriptional suppression of E-cadherin is a possible mechanism. DAXX/ZEB-1 pathway could be a potential therapeutic target for preventing cancer metastasis in CRC.

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Significance of E-cadherin and CD44 expression in patients with unresectable metastatic colorectal cancer

Cited by 23 publications

References 36 publications

Annexin A9 promotes invasion and metastasis of colorectal cancer and predicts poor prognosis

Annexin A9 promotes invasion and metastasis of colorectal cancer and predicts poor prognosis

<p>The Association Between Inflammation, Epithelial Mesenchymal Transition and Stemness in Colorectal Carcinoma</p>

Death Domain-Associated Protein Promotes Colon Cancer Metastasis through Direct Interaction with ZEB1

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