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Transgelin is a poor prognostic factor associated with advanced colorectal cancer (CRC) stage promoting tumor growth and migration in a TGF?-dependent manner.

ABSTRACT: Colorectal cancer (CRC) is the fourth most common cancer type globally. Investigating the signaling pathways that maintain cancer cell phenotype can identify new biomarkers for targeted therapy. Aberrant transforming growth factor-? (TGF?) signaling has been implicated in CRC progression, however, the exact mechanism by which TGF? exerts its function is still being unraveled. Herein, we investigated TAGLN expression, prognostic value, and its regulation by TGF? in CRC. While TAGLN was generally found to be downregulated in CRC, elevated expression of TAGLN was associated with advanced CRC stage and predicted poor overall survival (hazard ratio (HR)?=?1.8, log-rank test P-value?=?0.014) and disease-free survival (HR?=?1.6, log-rank test P-value?=?0.046), hence implicating TAGLN as poor prognostic factor in CRC. Forced expression of TAGLN was associated with enhanced CRC cell proliferation, clonogenic growth, cell migration and in vivo tumor formation in immunocompromised mice, while targeted depletion of TAGLN exhibited opposing biological effects. Global gene expression profiling of TAGLN-overexpressing or TAGLN-deficient CRC cell lines revealed deregulation of multiple cancer-related genes and signaling pathways. Transmission electron microscopy (TEM) revealed ultrastructural changes due to loss of TAGLN, including disruption of actin cytoskeleton organization and aberrant actin filament distribution. Hierarchical clustering, principle component, and ingenuity pathway analyses revealed distinct molecular profile associated with TAGLNhigh CRC patients with remarkable activation of a number of mechanistic networks, including SMARCA4, TGF?1, and P38 MAPK. The P38 MAPK was the top predicted upstream regulator network promoting cell movement through regulation of several intermediate molecules, including TGF?1. Concordantly, functional categories associated with cellular movement and angiogenesis were also enriched in TAGLNhigh CRC, supporting a model for the molecular mechanisms linking TGF?-induced upregulation of TAGLN and CRC tumor progression and suggesting TAGLN as potential prognostic marker associated with advanced CRC pathological stage.

SUBMITTER: Elsafadi M

PROVIDER: S-EPMC7214449 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Transgelin is a poor prognostic factor associated with advanced colorectal cancer (CRC) stage promoting tumor growth and migration in a TGFβ-dependent manner.

Elsafadi Mona M Manikandan Muthurangan M Almalki Sami S Mahmood Amer A Shinwari Tasneem T Vishnubalaji Radhakrishnan R Mobarak Mohammad M Alfayez Musaad M Aldahmash Abdullah A Kassem Moustapha M Alajez Nehad M NM

Cell death & disease 20200511 5

Colorectal cancer (CRC) is the fourth most common cancer type globally. Investigating the signaling pathways that maintain cancer cell phenotype can identify new biomarkers for targeted therapy. Aberrant transforming growth factor-β (TGFβ) signaling has been implicated in CRC progression, however, the exact mechanism by which TGFβ exerts its function is still being unraveled. Herein, we investigated TAGLN expression, prognostic value, and its regulation by TGFβ in CRC. While TAGLN was generally ...[more]

PMID: 32393769

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Project description:Background: Heterogeneous clinical and molecular characteristics are reported in colorectal cancer (CRC) with different tumor laterality. However, the outcome of left- and right-sided patients with stage I-III CRC and the role of chronic inflammation in survival differences between them remain unclear. Method: A prospective study including 1,181 surgical patients with stage I-III CRC was carried out to investigate the involvement of circulating fibrinogen-to-pre-albumin (Alb) ratio (FPR) and primary tumor sidedness in the clinical outcome of those patients. We further investigated the effect of FPR on adjuvant chemotherapy response and recurrence in stage III patients. Results: Our study showed that the right tumor location was significantly associated with poor recurrence-free survival (RFS) (p = 0.04, adjusted HR = 1.41, 95% CI = 1.02-1.94) and overall survival (OS) (p = 0.04, adjusted HR = 1.55, 95% CI = 1.01-2.38) only in the stage III disease. In these patients, T4 stage distribution (83.39 vs. 70.94%, p < 0.01) within right-sided cases was significantly higher than left-sided patients. Moreover, preoperative FPR within right-sidedness (p < 0.01), T4 stage (p < 0.05), and large cancer bulk (≥5 cm) (p < 0.05) subgroups was significantly elevated compared to their counterparts, and it was gradually rising following the increased cancer bulk (p trend < 0.01). High-FPR distribution (52.30 vs. 27.00%, p < 0.01) within right-sided patients with the stage III disease was significantly higher than that in the left-sided cases. RFS (p log-rank < 0.01) and OS (p log-rank < 0.01) of the high-FPR patients were extremely inferior to the low-FPR cases, and the significant associations were observed when they were adjusted by other confounders including primary tumor location (p < 0.01, adjusted HR = 1.96, 95% CI = 1.42-2.70 for RFS; p < 0.01, adjusted HR = 2.44, 95% CI = 1.59-3.75 for OS). Additionally, RFS of adjuvant chemotherapy-treated high-FPR patients was superior to the patients without chemotherapy (p log-rank = 0.01) but was inferior to the low-FPR patients undergoing the treatment, especially in the 5-FU- and XELOX-treated subgroup. Conclusion: These findings indicate that chronic high-grade inflammation weakens chemotherapy efficacy and contributes to the poor prognosis of stage III surgical CRC patients.

Dataset Information

Transgelin is a poor prognostic factor associated with advanced colorectal cancer (CRC) stage promoting tumor growth and migration in a TGF?-dependent manner.

Publications

Transgelin is a poor prognostic factor associated with advanced colorectal cancer (CRC) stage promoting tumor growth and migration in a TGFβ-dependent manner.

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