Tuberculous Fibrosis Enhances Tumorigenic Potential via the NOX4–Autophagy Axis

SIMPLE SUMMARY: Although previous studies have reported coexistence of pulmonary TB and carcinoma, the underlying mechanism of tuberculous fibrosis-induced tumorigenicity remains to be investigated. We previously reported that NOX4 signaling mediates tuberculous pleural fibrosis by activating ERK–ROS–EMT pathways. We were interested in the role of NOX4 in the tumor microenvironment changed by tuberculosis fibrosis. Our results showed that lung cancer cells enhanced the NOX4 expression and invasive potential after exposure to the conditioned medium of heat-killed Mycobacterium tuberculosis stimulated mesothelial cells or tuberculous pleural effusion. NOX4–autophagy signaling axis contributes to the interaction between tuberculosis fibrosis and lung cancer. Silencing of NOX4 signaling in tuberculous fibrosis reduced the metastatic potential by enhancing autophagy in both in vivoand in vitro studies. This result suggests that NOX4-P62 might serve as a therapeutic target for tuberculous fibrosis-associated lung cancer. ABSTRACT: While a higher incidence of lung cancer in subjects with previous tuberculous infection has been reported in epidemiologic data, the mechanism by which previous tuberculosis affects lung cancer remains unclear. We investigated the role of NOX4 in tuberculous pleurisy-assisted tumorigenicity both in vitro and in vivo.Heat-killed Mycobacterium tuberculosis-stimulated mesothelial cells augmented the migrationand invasive potential of lung cancer cells in a NOX4-dependent manner. Mice with Mycobacterium bovis bacillus Calmette–Guérin (BCG) pleural infection exhibited increased expression of NOX4 and enhanced malignant potential of lung cancer compared to mice with intrathoracic injection of phosphate-buffered saline. The BCG+ KLN205 (KLN205 cancer cell injection after BCG treatment) NOX4 KO mice group showed reduced tuberculous fibrosis-promoted metastatic potential of lung cancer, increased autophagy, and decreased expression of TGF-β, IL-6, and TNF-α compared to the BCG+KLN205 WT mice group. Finally, NOX4 silencing mitigated the malignant potential of A549 cells that was enhanced by tuberculous pleural effusion and restored autophagy signaling. Our results suggest that the NOX4–autophagy axis regulated by tuberculous fibrosis could result in enhanced tumorigenic potential and that NOX4-P62 might serve as a target for tuberculous fibrosis-induced lung cancer.