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C4.4A is associated with tumor budding and epithelial-mesenchymal transition of colorectal cancer.

ABSTRACT: C4.4A is a glycolipid-anchored membrane protein expressed in several human malignancies. The aim of this study was to explore the association between C4.4A expression at the invasion front of colorectal cancer (CRC) and tumor budding, a putative hallmark of cell invasion of CRC. Advanced CRCs (T2-4, n = 126) had a budding count of 3.66 ± 5.66, which was significantly higher than that of T1 early CRCs (1.75 ± 2.78, n = 87). C4.4A-positive CRC specimens showed a larger budding cell number than C4.4A-negative CRC specimens in T1 CRCs, and especially advanced CRCs (9.45 ± 5.83 vs 1.60 ± 3.93). Furthermore, we found a correlation between the percentage of C4.4A-positive cases and budding count in advanced CRC. Multivariate analysis for patients' survival showed that C4.4A was superior to tumor budding as a prognostic factor. With siRNA treatment, C4.4A levels were associated with cell invasion, but not with proliferation, in HCT116 and DLD1 cell lines. An immunohistochemical study in a subset of CRCs showed no relationship between C4.4A and Ki-67 proliferation marker. In vitro assays using HCT116 indicated that C4.4A levels correlated well with epithelial-mesenchymal transition (EMT) with regard to cell morphology and alterations of EMT markers including E-cadherin, vimentin, and partially N-cadherin. We also found that C4.4A expression was significantly associated with loss of E-cadherin and gain of ?-catenin in clinical CRC tissue samples. These findings suggest that a tight association between C4.4A and tumor budding may, in part, be due to C4.4A promoting EMT at the invasive front of CRC.

SUBMITTER: Oshiro R

PROVIDER: S-EPMC7685091 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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C4.4A is associated with tumor budding and epithelial-mesenchymal transition of colorectal cancer.

Oshiro Ryota R Yamamoto Hirofumi H Takahashi Hidekazu H Ohtsuka Masahisa M Wu Xin X Nishimura Junichi J Takemasa Ichiro I Mizushima Tsunekazu T Ikeda Masataka M Sekimoto Mitsugu M Matsuura Nariaki N Doki Yuichiro Y Mori Masaki M

Cancer science 20120411 6

C4.4A is a glycolipid-anchored membrane protein expressed in several human malignancies. The aim of this study was to explore the association between C4.4A expression at the invasion front of colorectal cancer (CRC) and tumor budding, a putative hallmark of cell invasion of CRC. Advanced CRCs (T2-4, n = 126) had a budding count of 3.66 ± 5.66, which was significantly higher than that of T1 early CRCs (1.75 ± 2.78, n = 87). C4.4A-positive CRC specimens showed a larger budding cell number than C4. ...[more]

PMID: 22404718

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Project description:Tumor‑stroma interactions serve a crucial role in the development of colorectal cancer (CRC), in which secreted protein acidic and rich in cysteine (SPARC) has been implicated. Due to interactions between cancer and stromal cells [mesenchymal stem cells (MSCs)], SPARC gene expression is markedly upregulated in CRC cells. The present study investigated the role of SPARC in CRC development and its potential as a biomarker. Specifically, the present study examined the association between SPARC expression and clinicopathological characteristics in 42 cases of CRC. SPARC expression in cancer cells was associated with T grade, N grade (TNM classification), stage and poor prognosis. Furthermore, the area of fibroblast‑activating protein‑positive staining around the cancer cells was increased in SPARC‑positive compared with SPARC‑negative cases. Proliferation and wound healing assays in SPARC‑silenced KM12SM cells [short hairpin RNA SPARC (shSPARC)], the reduced SPARC expression of which was demonstrated by reverse transcription‑quantitative PCR, revealed that the proliferative and migratory capacity of shSPARC cells did not differ from that of wild‑type (WT) cells. However, it was markedly reduced when co‑cultured with MSCs. Furthermore, in vivo, immunohistological analysis and RNA sequencing were conducted in an orthotopic implanted mouse model. Tumor growth and lymph node metastasis were markedly suppressed in shSPARC‑transplanted tumors compared with WT‑transplanted tumors, with a more marked suppression observed following shSPARC co‑transplantation with MSCs. Immunohistological examination further revealed that the stromal reaction and epithelial‑mesenchymal transition (EMT) were markedly suppressed in tumors co‑transplanted with shSPARC and MSCs, and these results were consistent with RNA sequencing using RNA extracted from orthotopic tumors. Overall, these results suggested that SPARC expression in CRC cells is dependent on the interaction between cancer cells and stromal cells to induce EMT and promote stromal formation in the tumor microenvironment, suggesting its suitability as a novel target molecule for CRC treatment.

Dataset Information

C4.4A is associated with tumor budding and epithelial-mesenchymal transition of colorectal cancer.

Publications

C4.4A is associated with tumor budding and epithelial-mesenchymal transition of colorectal cancer.

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