Transgelin is a poor prognostic factor associated with advanced colorectal cancer (CRC) stage promoting tumor growth and migration in a TGF\u03b2-dependent manner

Mona Elsafadi,Mohammad Mobarak,Amer Mahmood,Abdullah Aldahmash,Muthurangan Manikandan,Sami Almalki,Moustapha Kassem,Tasneem Shinwari,Radhakrishnan Vishnubalaji,Nehad M Alajez,Musaad Alfayez

doi:10.1038/s41419-020-2529-6

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-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 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, TGFβ1, and P38 MAPK. The P38 MAPK was the top predicted upstream regulator network promoting cell movement through regulation of several intermediate molecules, including TGFβ1. Concordantly, functional categories associated with cellular movement and angiogenesis were also enriched in TAGLNhigh CRC, supporting a model for the molecular mechanisms linking TGFβ-induced upregulation of TAGLN and CRC tumor progression and suggesting TAGLN as potential prognostic marker associated with advanced CRC pathological stage.

Highlights

Colorectal cancer (CRC) is one of the most common malignancies worldwide[1]
Functional categories associated with cellular movement and angiogenesis were enriched in TAGLNhigh CRC, supporting a model for the molecular mechanisms linking transforming growth factor-β (TGFβ)-induced upregulation of TAGLN and CRC tumor progression and suggesting TAGLN as potential prognostic marker associated with advanced CRC pathological stage
We performed Small-interfering RNA (siRNA)-mediated loss-of-function of TAGLN expression in the RKO CRC line, which has higher basal TAGLN expression (Fig. 2a). siTAGLN transfection led to substantial reduction in TAGLN expression in the RKO model (Fig. 2c)

Summary

Introduction

Colorectal cancer (CRC) is one of the most common malignancies worldwide[1]. In addition to conventional histopathological phenotyping, recent years have witnessed increased interest in utilizing genetic and molecular signatures as prognostic and predictive biomarkers to identify patients at high risk of progression and Official journal of the Cell Death Differentiation AssociationElsafadi et al Cell Death and Disease (2020)11:341recurrence[2,3]. In addition to conventional histopathological phenotyping, recent years have witnessed increased interest in utilizing genetic and molecular signatures as prognostic and predictive biomarkers to identify patients at high risk of progression and Official journal of the Cell Death Differentiation Association. Molecular profiling led to the identification of a number of signaling pathways associated with CRC, where targeting such pathways demonstrated increased clinical efficacy[4,5]. The role of TGFβ1, which is ubiquitously expressed, in cancer development and progression has been extensively studied. In CRC, TGFβ signaling exhibits contradicting effect either as a suppressor or as a stimulator, based on the cancer stage. TGFβ plays an inhibitory role on tumor cell growth and proliferation by inducing

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Conclusion