Abstract
Meta-analysis revealed that Leucine Zipper Down-Regulated In Cancer 1 (LDOC1) increased methylation more in people with lung tumors than in those who were healthy and never smoked. Quantitative methylation-specific PCR revealed that cigarette smoke condensate (CSC) exposure drives LDOC1 promoter hypermethylation and silence in human bronchial cells. Immunohistochemistry studies showed that LDOC1 downregulation is associated with poor survival of patients with lung cancer. Loss and gain of LDOC1 functions enhanced and attenuated aggressive phenotypes in lung adenocarcinoma A549 and non–small cell lung carcinoma H1299 cell lines, respectively. We found that LDOC1 deficiency led to reinforcing a reciprocal loop of IL-6/JAK2/STAT3, through which LDOC1 mediates the cancer progression. LDOC1 knockdown considerably augmented tumorigenesis and the phosphorylation of JAK2 and STAT3 in vivo. Results from immunoprecipitation and immunofluorescent confocal microscopy indicated that LDOC1 negatively regulates JAK2 activity by forming multiple protein complexes with pJAK2 and E3 ubiquitin-protein ligase LNX1, and in turn, LDOC1 targets pJAK2 to cause ubiquitin-dependent proteasomal degradation. LDOC1 deficiency attenuates the interactions between LNX1 and pJAK2, leading to ineffective ubiquitination of pJAK2, which activates STAT3. Overall, our results elucidated a crucial role of LDOC1 in lung cancer and revealed how LDOC1 acts as a bridge between tobacco exposure and the IL-6/JAK2/STAT3 loop in this human malignancy.
Highlights
Lung cancer is a leading cause of cancer deaths in men and women
DNA methylation array data for 35 lung adenocarcinoma (LADC) and 26 healthy lungs from the Cancer Genome Atlas (TCGA) indicated that the methylation index of two probes mapped to LDOC1 CpG islands were significantly increased in LADC samples compared with healthy lung tissue (p = 0.001024 and 0.045721, respectively; Figure 1E)
These results indicated that downregulation of LDOC1 in lung cancer was associated with a poor prognosis, especially for shorter overall survival (OS), suggesting that LDOC1 is a potential biomarker for the clinical outcome of patients with lung cancer
Summary
Lung cancer is a leading cause of cancer deaths in men and women. Lung cancer is heterogeneous and is classified into two types, small-cell lung carcinomas and non-small-cell lung carcinomas (NSCLCs), based on tumor histology. LDOC1 is ubiquitously expressed in all tissues but downregulated or silenced in many cancer types—including cervical cancer [8], ovarian cancer [9], OSCC [3], papillary thyroid carcinoma [10], and osteosarcoma [11]. In these human cancers, LDOC1 functions as a tumor suppressor by inhibiting proliferation and metastasis and by inducing apoptosis. Given the close association between cigarette smoke and lung cancers, we proposed that LDOC1 may play a role in the pathogenesis of lung cancers
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