LKB1 inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling

Abstract

LKB1 loss-of-function mutations, observed in ∼30% of human lung adenocarcinomas, contribute significantly to lung cancer malignancy progression. We show that lysyl oxidase (LOX), negatively regulated by LKB1 through mTOR-HIF-1α signaling axis, mediates lung cancer progression. Inhibition of LOX activity dramatically alleviates lung cancer malignancy progression. Up-regulated LOX expression triggers excess collagen deposition in Lkb1-deficient lung tumors, and thereafter results in enhanced cancer cell proliferation and invasiveness through activation of β1 integrin signaling. High LOX level and activity correlate with poor prognosis and metastasis. Our findings provide evidence of how LKB1 loss of function promotes lung cancer malignancy through remodeling of extracellular matrix microenvironment, and identify LOX as a potential target for disease treatment in lung cancer patients.T he high mortality of lung cancer (1) is largely attributable to failure of early diagnosis and metastasis frequently observed at the time of diagnosis. Tumor suppressor loss of function is widely adopted in tumor initiation and progression. The roles of LKB1 as a tumor suppressor have emerged from the observation of increased risk of malignancy in gastrointestinal tract in PeutzJeghers syndrome (PJS) patients harboring germ-line LKB1 mutations (2, 3). Although rare in most types of human cancers (4, 5), LKB1 loss-of-function somatic mutations are frequently observed in human non-small-cell lung cancer (NSCLC) (6-10). Mice with oncogenic Kras G12D mutant develop lung tumors with long latency and low aggressiveness. Concomitant loss of Lkb1 significantly shortened the latency, increased tumor burden, and promoted lung cancer invasion and distant metastasis, comparable to that from p53 loss (6). Yet, the molecular mechanisms involved remain largely unknown.Cancer progression is a reciprocal process involving intimate interaction between tumor cells and tumor stroma, including extracellular matrix (ECM). ECM alteration and remodeling is one of the most frequently observed and most important events during malignancy progression, which subsequently modulates cell-matrix and cell-cell interaction and results in altered cell behavior (11). Increasing interests and efforts have been paid to those enzymes involved in ECM remodeling, among which lysyl oxidase (LOX) is of particular interest. LOX oxidizes lysine residues in collagen and elastin, resulting in covalent cross-linking and stabilization of these ECM structural components (12). Aberrant LOX expression or enzymatic activity has been linked to a variety of pathological conditions, including breast cancer and lung cancer (13)(14)(15)(16). LOX is associated with hypoxia in human breast cancer and head and neck tumors, and is responsible for hypoxiainduced tumor metastasis (13). Although studies have implicated deregulated LOX mRNA and protein levels in lung adenocarcinomas (17, 18), the roles and molecular mechanisms of LOX involved in lung cancer progression are poorly understood.Here we...

Expression and Significance of Hypoxia Inducible Factor-1α and Lysyl Oxidase in Non-small Cell Lung Cancer

“…One possible explanation of this disparity may be the small sample size included in that study. Our findings agree well with several previous studies (Gao et al, 2010;Wilgus et al, 2011), which demonstrating that higher expression of LOX is associated with invasion and is a predictor of poor prognosis in lung adenocarcinoma.…”

“…Therefore, aberrant LOX expression or enzymatic activity leads to a series of disease predominantly associated with the ECM, as well as in many human cancers. Increasing evidences have shown that LOX is linked to increased invasion and migration of hypoxic NSCLC cell lines in vitro (Sahlgren et al, 2008;Gao et al, 2010;Wei et al, 2012). However, whether there is some association between HIF-1α and LOX, and what role HIF-1α and LOX play in NSCLC has not previously been investigated.…”

Integrin-binding Protein Nischarin Interacts with Tumor Suppressor Liver Kinase B1 (LKB1) to Regulate Cell Migration of Breast Epithelial Cells

“…Our previous findings show that Nischarin inhibits anchorage-independent growth, which is inhibited by Nischarin (11). LKB1 has also been shown to inhibit anchorage-independent growth (32). Therefore, we asked whether Nischarin and LKB1 have a cooperative effect on inhibiting anchorage-independent growth.…”

Breaking the epithelial polarity barrier in cancer: the strange case of LKB1/PAR-4

“…Loss-of-function mutations in LKB1 are common in lung cancer and loss of LKB1 has been observed to correlate with significantly enhanced levels of LOX enzymes. In a mouse model of lung cancer and human non-small cell lung cancer cell lines, loss of LKB1 leads via enhanced mTOR and HIF1a signalling to enhanced LOX activity, increased deposition of collagen and enhanced proliferation possibly caused by increased matrix stiffness [94]. Thus, although the physiological significance of LKB1-LOX crosstalk remains unclear, loss of LKB1 and the consequent dysregulation of LOX activity in the context of tumour tissue has a prominent impact on stromal extracellular matrix remodelling and collagen biology ( figure 3).…”

“…Breakdown of BM is considered an essential step for tumour invasion and metastases. However, loss of LKB1 may also exert opposite, stabilizing effects on BMs and extracellular matrix by stimulating expression of the collagen cross-linking enzyme LOX [94]. Also, these effects may benefit tumour progression, at least once the tumour has breached the BM barrier, by increasing the stiffness of the extracellular matrix.…”