Hypoxia‑induced galectin‑3 enhances RhoA function to activate the motility of tumor cells in non‑small cell lung cancer

Abstract

Galectin-3 plays crucial roles in tumor progression. However, in non-small cell lung cancer (NSCLC), it remains unclear whether the hypoxic tumor microenvironment enhances galectin-3-induced cell motility. We investigated galectin-3 expression in NSCLC cells under hypoxia, and the possible molecular mechanisms by which galectin-3 influences tumor aggressiveness. Galectin-3 levels in NSCLC cell lines under hypoxia were assessed using reverse transcription PCR and western blotting. To clarify the role of endogenous galectin-3, the effect of galectin-3 knockdown in NSCLC cells was investigated using scratch and invasion assays. The expression and clinicopathological significance of galectin-3 in 57 patients with pN0M0 invasive pulmonary adenocarcinoma were investigated by immunohistochemistry. Both mRNA and protein levels of galectin-3 in the NSCLC cell lines A549 and LK-2 were upregulated by hypoxia. As revealed by scratch and invasion assays, the cell migratory and invasive activities were significantly increased under hypoxia, but were reduced by galectin-3 knockdown. Notably, addition of galectin-3 to the media did not improve the cell motility impaired by galectin-3 knockdown. To clarify the role of endogenous galectin-3 in the enhancement of tumor cell motility under hypoxia, we focused on the function of RhoA. RhoA level in the plasma membrane, but not in the cytoplasm, was increased under hypoxia and decreased by galectin-3 knockdown. RhoA activity was significantly enhanced under hypoxia and effectively inhibited by galectin-3 knockdown. In patients with pN0M0 invasive pulmonary adenocarcinoma, higher galectin-3 expression on tumor cells was significantly associated with tumor cell invasion into microvessels and tumor recurrence after surgery. These data demonstrate that in NSCLC cells under hypoxia, upregulated galectin-3 levels increase the localization of RhoA to the plasma membrane, thus enhancing RhoA activity, which is associated with aggressive cell motility. In pN0M0 invasive pulmonary adenocarcinoma, galectin-3 is a potential biomarker for predicting tumor recurrence after radical surgery.

Galectin-3 protects against ischemic stroke by promoting neuro-angiogenesis via apoptosis inhibition and Akt/Caspase regulation

“…[47][48][49][50] Gal3 is one of the major active components of the low oxygen/ischemic environment. 51,52 We have shown significant up-regulation of Gal3 in the post-stroke rat brain. Furthermore, blocking of Gal3 with neutralizing antibody decreased the cerebral blood vessel density.…”

“…There is an emerging body of evidence that Gal3 is upregulated under a hypoxic micro-environment due to vaso-occlusion or defective angiogenesis, particularly in solid tumors to enhance their survival, growth, and invasion. 51–63 Gal3 is also associated with cognitive impairment and aging. 64 Despite these compelling data, the specific role of Gal3 in post-stroke brain has not been systematically elucidated.…”

Inhibition of galectin‐3 augments the antitumor efficacy of PD‐L1 blockade in non‐small‐cell lung cancer

“…Kataoka et al . [41] reported that hypoxia could increase the expression of Gal‐3 in NSCLC cells and thus contributes to metastasis. In esophageal cancer, Gal‐3 can promote cancer progression through activation of the AKT/ERK pathway [42], while Yao et al .…”

“…In addition, Gal-3 may directly promote cancer progression and metastasis through multiple pathways. Kataoka et al [41] reported that hypoxia could increase the expression of Gal-3 in NSCLC cells and thus contributes to metastasis. In esophageal cancer, Gal-3 can promote cancer progression through activation of the AKT/ERK pathway [42], while Yao et al [43] reported that, in pancreatic cancer, inhibition of Gal-3 blocked the AKT/FOXO3 signaling pathway and subsequently suppressed cancer progression.…”

Galectin-3 Expression in Pancreatic Cell Lines Under Distinct Autophagy-Inducing Stimulus

“…Cultivation of PANC-1 cells under the hypoxic/nutrient-deprived condition not only stimulates autophagy but modulates positively the Gal-3 expression. Gal-3 upregulation under hypoxic exposure has been reported for other tumors as breast (de Oliveira et al, 2015), thyroid (Zheng et al, 2017), and non-small-cell lung carcinoma (Kataoka et al, 2019). Previous results of our research group brought the upregulation of mRNA Gal-3 when PANC-1 cells undergone hypoxic incubation (da Silva Filho et al, 2020).…”