Abstract
High mobility group box 1 (HMGB1) has been demonstrated to promote the migration and invasion of non-small cell lung cancer (NSCLC). However, the mechanism of action of HMGB1 in regulating tumor mobility remains unclear. Therefore, we aimed to investigate whether HMGB1 affects mitochondria distribution and regulates dynamin-related protein 1 (DRP1)-mediated lamellipodia/filopodia formation to promote NSCLC migration. The regulation of mitochondrial membrane tension, dynamics, polarization, fission process, and cytoskeletal rearrangements in lung cancer cells by HMGB1 was analyzed using confocal microscopy. The HMGB1-mediated regulation of DRP1 phosphorylation and colocalization was determined using immunostaining and co-immunoprecipitation assays. The tumorigenic potential of HMGB1 was assessed in vivo and further confirmed using NSCLC patient samples. Our results showed that HMGB1 increased the polarity and mobility of cells (mainly by regulating the cytoskeletal system actin and microtubule dynamics and distribution), promoted the formation of lamellipodia/filopodia, and enhanced the expression and phosphorylation of DRP1 in both the nucleus and cytoplasm. In addition, HMGB1 and DRP1 expressions were positively correlated and exhibited poor prognosis and survival in patients with lung cancer. Collectively, HMGB1 plays a key role in the formation of lamellipodia and filopodia by regulating cytoskeleton dynamics and DRP1 expression to promote lung cancer migration.
Highlights
With advancements in medical diagnosis, the survival rate of cancer patients has improved, except for that of lung cancer, where late diagnosis is the primary reason for a five-year survival rate of less than 5% [1]
Since High mobility group box 1 (HMGB1) increased mitochondrial fission, we further examined whether HMGB1 affected dynamin-related protein 1 (DRP1) expression and mitochondria shape
We demonstrated that DRP1 accumulates in the nucleus and cytoplasm in the LV-HMGB1 group
Summary
With advancements in medical diagnosis, the survival rate of cancer patients has improved, except for that of lung cancer, where late diagnosis is the primary reason for a five-year survival rate of less than 5% [1]. Though low-dose computed tomography (LDCT) screening has improved the five-year survival rate of patients with lung cancer, the usage of LDCT is not widely promoted [2]. High mobility group box 1 (HMGB1) with a genetic location on the 13q12.3 chromosome belongs to the high mobility group box superfamily. It is a DNA-binding protein that regulates several cellular processes, such as inflammation, cell differentiation, and tumor cell migration [4]. HMGB1 was shown to increase matrix metalloproteinase-9 expression through the phosphatidylinositol 3-kinase/protein kinase B and nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathways, and it was found to promote lung cancer migration, invasion, and metastasis [12]
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