Leukotriene A4 hydrolase (LTA4H), an inflammatory mediator, has garnered attention for its role in the development of chronic lung diseases and various cancers. Our study highlights the protective role of LTA4H in hepatocellular carcinoma (HCC) occurrence and progression. LTA4H is downregulated in clinical and mouse HCC tumors. LTA4H deficiency exacerbates hepatocyte damage by restraining JNK activation and promotes CD206 + macrophage polarization through the upregulation of LTBP1 expression and downstream transforming growth factor β (TGF-β) secretion and activation. Mechanistically, LTA4H induces heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) phosphorylation, enhancing their interaction and leading to the functional inhibition of HNRNPA1 in regulating Ltbp1 mRNA maturation and processing in the nucleus. LTA4H-deficient patients exhibit poor prognosis and immunotherapy resistance. Combination therapy targeting TGF-β and PD-1 significantly improves the immunotherapy resistance of LTA4H-knockout Hepa1-6 tumors. Our findings reveal the previously unreported role of LTA4H in regulating the tumor microenvironment and provide insights into potential diagnostic and therapeutic strategies for patients with LTA4H-deficient HCC.
Xingxia Wan,Huiling Wang,Baotang Shi,Yu Guo,Shi-Yu Liu,Xianwang Wang
Early diagnosis of cancer is an efficient strategy to prevent tumor progression and improve the survival rate of patients. However, to discovery of reliable tumor-specific biomarkers remains a great challenge. Leukotriene A4 hydrolase (LTA 4 H) is a bifunctional zinc metalloenzyme with epoxide hydrolase activity and aminopeptidase activity, which plays important roles in allergic and inflammatory reactions and showed strong relevance with carcinoma progression. We thus sought to investigate the possibility of application LTA 4 H activity detection in cancer diagnosis. To achieve this, we herein develop an enzyme activated fluorescent probe for LTA 4 H activity sensing by incorporating the specific recognition unit of LTA 4 H with a red-emitting fluorophore. The acquired probe (named as ADMAB ) showed high sensitivity and specificity toward LTA 4 H in vitro . By further application of ADMAB in living cells, significantly elevated LTA 4 H activity in cancer cell lines was observed when compared with normal cell lines and in vivo tracing A549 tumor in nude mice was also realized by ADMAB . Meanwhile, the wound-healing assay further revealed the importance of LTA 4 H in tumor metastasis. Moreover, the LTA 4 H activity in human serum sample was successfully detected by ADMAB and significantly elevated LTA 4 H activity in patients diagnosed with cancer was firstly found, which demonstrated ADMAB to be a useful tool for cancer diagnosis and LTA 4 H related biological study.
Severe atmospheric haze caused by industrial pollution has severely affected human health and led to the increasing incidence of cardiopulmonary diseases, including pneumonia. Conventional methods for diagnosis of pneumonia are complicated and tedious, and current clinical imaging techniques might cause organ injuries to some extent. Therefore, an accurate, fast, and intact imaging method must be developed to diagnose pneumonia in the early stages. In this study, we propose a new two-photon fluorescence probe, named as ASPC, for detection of the activity of the inflammatory biomarker LTA4H through specific recognition and cleavage of amides containing the unnatural amino acid l-AspBzl. The activity of LTA4H in the lung tissues of mice was rapidly and accurately monitored for the first time and could be an indicator for diagnosis of pneumonia. The severity of pneumonia in mice caused by haze particulate was determined through imaging the activity of LTA4H as biomarker and confirmed using a commercial ELISA kit of interleukin-1β. This work provides a promising method for clinical detection of pneumonia and for screening specific depressors of LTA4H as potential drug candidates.
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