Lysyl oxidase-like 2 is critical to tumor microenvironment and metastatic niche formation in hepatocellular carcinoma

Abstract

Poor prognosis of cancers, including hepatocellular carcinoma (HCC), is mainly associated with metastasis; however, the underlying mechanisms remain poorly understood. This article investigates the role of lysyl oxidase-like 2 (LOXL-2) in the biology of HCC metastasis. First, we showed that HCC metastasis relies on a collagen-modifying enzyme, LOXL2, which was significantly overexpressed in tumorous tissues and sera of HCC patients, indicating that LOXL2 may be a good diagnostic marker for HCC patients. Second, we delineated a complex, interlinked signaling network that involves multiple regulators, including hypoxia, transforming growth factor beta (TGF-b), and microRNAs (miRNAs), converging to control the expression of LOXL2. We found not only that LOXL2 was regulated by hypoxia/hypoxia-inducible factor 1 alpha (HIF-1a), but also that TGF-b activated LOXL2 transcription through mothers against decapentaplegic homolog 4 (Smad4), whereas two frequently underexpressed miRNA families, miR-26 and miR-29, cooperatively suppressed LOXL2 transcription through interacting with the 3' untranslated region of LOXL2. Third, we demonstrated the imperative roles of LOXL2 in modifying the extracellular matrix components in the tumor microenvironment and metastatic niche of HCC. LOXL2 promoted intrahepatic metastasis by increasing tissue stiffness, thereby enhancing the cytoskeletal reorganization of HCC cells. Furthermore, LOXL2 facilitated extrahepatic metastasis by enhancing recruitment of bone-marrow-derived cells to the metastatic site. Conclusion: These findings integrate the clinical relevance, molecular regulation, and functional implications of LOXL2 in HCC metastasis. (HEPATOLOGY 2014;60:1645-1658 H epatocellular carcinoma (HCC) is the most common form of primary liver cancer. HCC is the fifth-most prevalent cancer and ranked the second-most common lethal cancer.1 It claims more than 600,000 lives globally every year. 1 The high mortality rate in HCC is mainly attributable to metastasis for at least three reasons. First, it is a major cause of liver and organ failure. Second, patients diagnosed

Transketolase counteracts oxidative stress to drive cancer development

“…pLKO.1-puro vectors encompassing shRNA targeting TKT, NRF2, KEAP1, BACH1 (Table S2), or a nontarget control (Sigma Aldrich) were stably transfected into HCC cell lines by a lentiviral-mediated approach, as we previously described (39). HCC cells that stably expressed the vectors were selected by puromycin.…”

Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma

“…HCC cell lines with stable knockdowns were produced using a lentiviral-mediated approach as previously described (49)(50)(51). In short, pLKO.1-puro vectors encompassing shRNAs targeting MTHFD1L (shMTHFD1L), NRF2 (shNRF2), or a nontarget control were stably transfected into HCC cell lines.…”

Lysine-Specific Histone Demethylases Contribute to Cellular Differentiation and Carcinogenesis

“…Different human cancers show an LOXL2 up-regulation [178,179] that correlates with tumor grade, poor prognosis, and decreased survival [168]. In fact, a possible role for LOXL2 in pre-metastatic niche formation has been suggested [180]. Further, LOXL2 can modify the extracellular matrix components in the tumor …”

“…Different human cancers show an LOXL2 up-regulation [178,179] that correlates with tumor grade, poor prognosis, and decreased survival [168]. In fact, a possible role for LOXL2 in pre-metastatic niche formation has been suggested [180]. Further, LOXL2 can modify the extracellular matrix components in the tumor microenvironment and metastatic niche of HCCs and promote intrahepatic metastasis by increasing tissue stiffness, thereby enhancing the cytoskeletal reorganization of HCC cells [180] Additionally, LOXL2 facilitates extrahepatic metastasis by enhancing recruitment of bone marrow-derived cells to the metastatic site [180].…”

“…In fact, a possible role for LOXL2 in pre-metastatic niche formation has been suggested [180]. Further, LOXL2 can modify the extracellular matrix components in the tumor microenvironment and metastatic niche of HCCs and promote intrahepatic metastasis by increasing tissue stiffness, thereby enhancing the cytoskeletal reorganization of HCC cells [180] Additionally, LOXL2 facilitates extrahepatic metastasis by enhancing recruitment of bone marrow-derived cells to the metastatic site [180]. Finally, since LOXL2 plays a key role during EMT (as described above), alterations of LOXL2 could increase the metastatic progression of cancer cells by affecting this process.…”