The SLIT/ROBO Pathway in Liver Fibrosis and Cancer

Abstract

Liver fibrosis is a common outcome of most chronic liver insults/injuries that can develop into an irreversible process of cirrhosis and, eventually, liver cancer. In recent years, there has been significant progress in basic and clinical research on liver cancer, leading to the identification of various signaling pathways involved in tumorigenesis and disease progression. Slit glycoprotein (SLIT)1, SLIT2, and SLIT3 are secreted members of a protein family that accelerate positional interactions between cells and their environment during development. These proteins signal through Roundabout receptor (ROBO) receptors (ROBO1, ROBO2, ROBO3, and ROBO4) to achieve their cellular effects. The SLIT and ROBO signaling pathway acts as a neural targeting factor regulating axon guidance, neuronal migration, and axonal remnants in the nervous system. Recent findings suggest that various tumor cells differ in SLIT/ROBO signaling levels and show varying degrees of expression patterns during tumor angiogenesis, cell invasion, metastasis, and infiltration. Emerging roles of the SLIT and ROBO axon-guidance molecules have been discovered in liver fibrosis and cancer development. Herein, we examined the expression patterns of SLIT and ROBO proteins in normal adult livers and two types of liver cancers: hepatocellular carcinoma and cholangiocarcinoma. This review also summarizes the potential therapeutics of this pathway for anti-fibrosis and anti-cancer drug development.

YTHDF2 favors protumoral macrophage polarization and implies poor survival outcomes in triple negative breast cancer

“… 50 , 51 , 52 , 53 SPI1 committed macrophage maturation and reprogramming by ROBO signaling pathway ( Figure S7 A). 54 , 55 , 56 XBP1 favored the synthesis and secretion of cholesterol to cause immunosuppression, as well as regulating pro-tumoral macrophages signaled by WNT in cancer ( Figure S7 B). 57 , 58 , 59 The rest of the TFs also presented similar patterns ( Figures S7 C‒S7H).…”

Gene Signature Associated with Nervous System in an Experimental Radiation- and Estrogen-Induced Breast Cancer Model

“…Recent studies have shown that distinct tumor cells display varying expression patterns at different stages of tumor angiogenesis, cell invasion, metastasis, and infiltration, in addition to varying levels of SLIT/ROBO signaling. The SLIT and ROBO axon-guidance molecules are now known to perform new functions in the onset of liver fibrosis and cancer [55]. ROBO1 has been implicated as a tumor suppressor for various types of cancer, including breast cancer, and the transmembrane proline-rich γ-carboxyglutamic acid protein 4 (PRRG4) may be a novel target for treating metastatic breast cancer; however, the regulation of ROBO1 expression during tumorigenesis remains poorly understood.…”

The nerve cells in gastrointestinal cancers: from molecular mechanisms to clinical intervention

“…In precancerous intestinal lesions and during tumor progression, Slit2/Robo1 signaling triggers the Wnt/β-catenin pathway by down-regulating E-cadherin and induces EMT [ 61 ]. In HCC, ESCC, PDAC and GC, the Robo1 signaling axis activation can promotes cancer progression, and metastasis [ 63 – 67 ]. Conversely, deubiquitinating and stabilizing ROBO1 in CRC can inhibit tumor migration [ 68 ].…”