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Long Noncoding RNA LIT3527 Knockdown induces Apoptosis and Autophagy through inhibiting mTOR pathway in Gastric Cancer Cells.

ABSTRACT: Gastric cancer is one of the most common cancers and the leading causes of cancer mortality. However, the molecular mechanisms of gastric cancer malignancy remain unclear. Long noncoding RNAs (lncRNAs) have been well documented in controlling cancer progression. Identification of critical lncRNAs in gastric cancer will provide new sights into the regulation mechanism of gastric cancer. Here, we screened differentially expressed lncRNAs in gastric cancer tissues and matched adjacent tissues and found that lncRNA LIT3527, a 486-nucleotide (nt) sense transcript, was frequently upregulated in gastric cancer tissues. Knockdown of LIT3527 dramatically suppressed proliferation and migration of gastric cancer cells through inducing severe cell death but not affecting cell cycle. Mechanistically, we uncovered that depletion of LIT35227 induced significant cell apoptosis and autophagy through inhibiting AKT/ERK/mTOR signaling pathway. Targeting LIT3527 showed a robust inhibition of lung metastasis of gastric cancer cells. Taken together, these results suggest that LIT3527 is essential for gastric cancer cell survival through maintaining mTOR activity, suggesting that it may be clinically valuable as a therapeutic target for gastric cancer.

SUBMITTER: Wang B

PROVIDER: S-EPMC8247385 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundIntervertebral disc degeneration results from a variety of etiologies, including inflammation and aging. Degenerated intervertebral discs feature down-regulated extracellular matrix synthesis, resulting in losing their ability to retain water and absorb compression. Celecoxib is a well-known selective cyclooxygenase-2 inhibitor for treating arthritis and relieving pain. Nevertheless, the mechanism of Celecoxib for treating inflammation-related intervertebral disc degeneration has not yet been clarified.MethodProtein synthesis was analyzed by western blot. Fluorescent probes DCFH-DA and MitoSox Red detected reactive oxygen species and were measured by flow cytometry. The activity of the kinase pathway was evaluated by protein phosphorylation. Autophagy was monitored by mRFP-GFP-LC3 transfection and LC3 analysis. Mitochondrial apoptotic proteins were analyzed by western blot and cell membrane integrity was measured by flow cytometry. The autophagic gene was silenced by siRNA.ResultsIn this study, interleukin-1β stimulation reduced the synthesis of aggrecan, type I and II collagen and caused excessive production of reactive oxygen species. We looked for a therapeutic window of Celecoxib for nucleus pulposus cells to regain extracellular matrix synthesis and reduce oxidative stress. To look into nucleus pulposus cells in response to stimuli, enhancement of autophagy was achieved by Celecoxib, confirmed by mRFP-GFP-LC3 transfection and LC3 analysis. The mammalian target of rapamycin and a panel of downstream proteins responded to Celecoxib and propelled autophagy machinery to stabilize homeostasis. Ultimately, inhibition of autophagy by silencing autophagy protein 5 disrupted the protective effects of Celecoxib, culminating in apoptosis.ConclusionIn summary, we have demonstrated a new use for the old drug Celecoxib that treats intervertebral disc degeneration by enhancing autophagy in nucleus pulposus cells and opening a door for treating other degenerative diseases.

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Long Noncoding RNA LIT3527 Knockdown induces Apoptosis and Autophagy through inhibiting mTOR pathway in Gastric Cancer Cells.

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