CTHRC1: a key player in colorectal cancer progression and immune evasion

Abstract

The multifunctional secreted protein, collagen triple helix repeat containing 1 (CTHRC1), has recently emerged as a significant focus within oncology research. CTHRC1 expression in tumors is governed by a complex interplay of regulatory signals, including methylation, glycosylation, and notably, non-coding RNAs, which constitute its predominant regulatory mechanism. Colorectal cancer (CRC), a highly prevalent epithelial malignancy, sees CTHRC1 influencing tumor progression and metastasis through its modulation of several downstream signaling cascades, such as Wnt/PCP, TGF-β/Smad, and MEK/ERK pathways. Furthermore, CTHRC1 contributes to immune evasion in CRC via diverse mechanisms. It is intricately associated with macrophage phenotypic switching within the tumor microenvironment (TME), favoring M2 macrophage polarization and facilitating the infiltration of T cells and neutrophils. CTHRC1 is also instrumental in immune escape by driving the remodeling of the extracellular matrix through interactions with cancer-associated fibroblasts. Additionally, CTHRC1's roles extend to the regulation of hypoxia-related pathways, metabolism of glycolysis and fatty acids, and involvement in tumor angiogenesis, all of which support tumor immune evasion. Considering its multifaceted activities, CTHRC1 emerges as a promising therapeutic target in CRC, with the potential to enhance the outcomes of existing radiotherapeutic and immunotherapeutic regimens. This review endeavors to delineate the mechanistic and therapeutic landscapes of CTHRC1 in CRC. Through a comprehensive discussion of CTHRC1's diverse functions, we aim to provide insights that could pave the way for innovative approaches in cancer therapy.

Keywords: CTHRC1; colorectal cancer; immune evasion; progression; therapy.

Figure 1

SP1 can directly bind to the promoter to activate miR-520d-5p. Both miR-155 and miR-520d-5p can target CTHRC1 to negatively regulate its expression. Let-7b-5p can negatively regulate the expression of CTHRC1, while HOXA11-AS can inhibit the function of let-7b-5p, thereby upregulating CTHRC1. Similarly, Linc00707 can negatively regulate miR-30c and can act as a molecular sponge to inhibit the function of miR-30c, thereby upregulating the expression of CTHRC1. MiR-30b can directly negatively regulate the expression of CTHRC1. LINC00518 upregulates the expression of CTHRC1 via the miR-335-3p/CTHRC1 axis. MiR-101 and miR-217 can negatively regulate MALAT-1, thereby negatively regulating the expression of CTHRC1.

Figure 2

Overexpression of CTHRC1 promotes the proliferation and migration of CRC cells through the Wnt/PCP, MEK/ERK, and TGF-β/Smad signaling pathways.

Figure 3

CTHRC1 can be secreted by CRC cells and CAFs. In CAFs, CTHRC1 can promote the deposition of ECM in the TME through the CTHRC1-POSTN-MMP13 axis. CTHRC1 can also promote the phenotype transformation of macrophages to M2 and recruit M2 macrophages through the ITGβ3 and TGF-β/Smad signaling pathways. M2-type macrophages promote tumor progression through the CXCL13/CXCR5/NFκB/p65 axis. Additionally, CTHRC1 can upregulate PD-L1 expression by regulating the expression of HIF-1α in response to hypoxic signals and modulate fatty acid metabolism and glycolysis. CTHRC1 can also promote angiogenesis. These roles of CTHRC1 in the TME collectively facilitate immune evasion of tumor cells.