Loss of Hyaluronan and Proteoglycan Link Protein-1 Induces Tumorigenesis in Colorectal Cancer.

Yao Wang,Jacqueline E Marshall,Yang Zhao,Muxue Gong,Gang Liu,Jincheng Xu,Xiaoyue Xu,Kamal Dua,Philip M Hansbro

doi:10.3389/fonc.2021.754240

Abstract

Colorectal cancer (CRC) is the third most common diagnosed cancer worldwide, but there are no effective cures for it. Hyaluronan and proteoglycan link protein-1 (HAPLN1) is a component of the extracellular matrix (ECM) proteins and involved in the tumor environment in the colon. Transforming growth factor (TGF)-β is a key cytokine that regulates the deposition of ECM proteins in CRC. However, the role of HAPLN1 in TGF-β contributions to CRC remains unknown. We found that the mRNA expression of HAPLN1 was decreased in tumors from CRC patients compared with healthy controls and normal tissue adjacent to the tumor using two existing microarray datasets. This was validated at the protein level by tissue array from CRC patients (n = 59). HAPLN1 protein levels were also reduced in human CRC epithelial cells after 24 h of TGF-β stimulation, and its protein expression correlated with type I collagen alpha-1 (COL1A1) in CRC. Transfection of HAPLN1 overexpression plasmids into these cells increased protein levels but reduced COL1A1 protein, tumor growth, and cancer cell migration. TGF-β stimulation increased Smad2/3, p-Smad2/3, Smad4, and E-adhesion proteins; however, HAPLN1 overexpression restored these proteins to baseline levels in CRC epithelial cells after TGF-β stimulation. These findings suggest that HAPLN1 regulates the TGF-β signaling pathway to control collagen deposition via the TGF-β signaling pathway and mediates E-adhesion to control tumor growth. Thus, treatments that increase HAPLN1 levels may be a novel therapeutic option for CRC.

Highlights

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide and the second most lethal with more than 900,000 deaths annually [1]
We found that Hyaluronan and proteoglycan link protein-1 (HAPLN1) mRNA was significantly decreased in CRC patients compared with healthy tissues (Figure 1A)
We found that low expression of the HAPLN1 gene in CRC patients correlated with shorter survival periods than those with high HAPLN1 expression (P = 0.035, Figure 1C)

Summary

Introduction

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide and the second most lethal with more than 900,000 deaths annually [1]. The number of new cases is predicted to reach 2.5 million in 2035 [1]. The 5-year survival rate of CRC is ~65%, but this drops to less than 10% at later stages [2]. The cause of tumor formation in CRC remains unknown. Polyps induce long-term inflammation in the colon and may contribute to tumor development of CRC [3]. Tissue microenvironment changes result in tumor formation in CRC.

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Conclusion