Inhibition of lysyl oxidase-like 2 overcomes adhesion-dependent drug resistance in the collagen-enriched liver cancer microenvironment

Research output: Journal Publications and ReviewsRGC 21 - Publication in refereed journalpeer-review

5 Scopus Citations
View graph of relations

Author(s)

  • Lanqi Gong
  • Yu Zhang
  • Yuma Yang
  • Qian Yan
  • Jie Luo
  • Yuen Chak Tiu
  • Xiaona Fang
  • Beilei Liu
  • Ka-On Lam
  • Anne Wing-Mui Lee
  • Xin-Yuan Guan

Related Research Unit(s)

Detail(s)

Original languageEnglish
Pages (from-to)3194-3211
Journal / PublicationHepatology Communications
Volume6
Issue number11
Online published27 Jul 2022
Publication statusPublished - Nov 2022

Link(s)

Abstract

The tumor microenvironment (TME) is considered to be one of the vital mediators of tumor progression. Extracellular matrix (ECM), infiltrating immune cells, and stromal cells collectively constitute the complex ecosystem with varied biochemical and biophysical properties. The development of liver cancer is strongly tied with fibrosis and cirrhosis that alters the microenvironmental landscape, especially ECM composition. Enhanced deposition and cross-linking of type I collagen are frequently detected in patients with liver cancer and have been shown to facilitate tumor growth and metastasis by epithelial-to-mesenchymal transition. However, information on the effect of collagen enrichment on drug resistance is lacking. Thus, the present study has comprehensively illustrated phenotypical and mechanistic changes in an in vitro mimicry of collagen-enriched TME and revealed that collagen enrichment could induce 5-fluorouracil (5FU) and sorafenib resistance in liver cancer cells through hypoxia-induced up-regulation of lysyl oxidase-like 2 (LOXL2). LOXL2, an enzyme that facilitates collagen cross-linking, enhances cell adhesion-mediated drug resistance by activating the integrin alpha 5 (ITGA5)/focal adhesion kinase (FAK)/phosphoinositide 3-kinase (PI3K)/rho-associated kinase 1 (ROCK1) signaling axis. Conclusion: We demonstrated that inhibition of LOXL2 in a collagen-enriched microenvironment synergistically promotes the efficacy of sorafenib and 5FU through deterioration of focal adhesion signaling. These findings have clinical implications for developing LOXL2-targeted strategies in patients with chemoresistant liver cancer and especially for those patients with advanced fibrosis and cirrhosis.

Research Area(s)

  • METASTATIC NICHE FORMATION, CAM-DR, LOXL2, PROMOTES, APOPTOSIS, CELLS, HCC, CHEMOTHERAPY, EXPRESSION, FIBROSIS

Citation Format(s)

Inhibition of lysyl oxidase-like 2 overcomes adhesion-dependent drug resistance in the collagen-enriched liver cancer microenvironment. / Gong, Lanqi; Zhang, Yu; Yang, Yuma et al.
In: Hepatology Communications, Vol. 6, No. 11, 11.2022, p. 3194-3211.

Research output: Journal Publications and ReviewsRGC 21 - Publication in refereed journalpeer-review

Download Statistics

No data available