Heat shock protein A12A activates migration of hepatocellular carcinoma cells in a monocarboxylate transporter 4-dependent manner

Cell Stress Chaperones. 2022 Jan;27(1):83-95. doi: 10.1007/s12192-021-01251-z. Epub 2022 Jan 20.

Abstract

Metastasis is responsible for most of the hepatocellular carcinoma (HCC)-associated death. However, its underlying mechanism has yet to be fully elucidated. Glycolysis-derived lactate has been shown to be a powerful regulator of cancer metastasis. Heat shock protein A12A (HSPA12A) encodes a novel member of HSP70 family. We have recently demonstrated that heat shock protein A12A (HSPA12A) inhibited renal cancer cell migration by suppressing lactate output and glycolytic activity, which were mediated by unstabilizing CD147 and promoting its degradation. By striking contrast, here we demonstrated that HSPA12A promoted migration of human HCC cells. Extracellular acidification, lactate export, and glycolytic activity in HCC cells were also promoted following HSPA12A overexpression. Further analysis revealed that HSPA12A interacted with MCT4 and increased its membrane localization, thereby promoting export of lactate generated from glycolysis; this led, ultimately, to HCC cell migration. Our results revealed the opposite effect of HSPA12A on migration of renal cancer cells and that of HCC cells. Of note, in contrast to the inhibitory effect on CD147 expression in renal cancer cells, we found that HSPA12A increased CD147 expression in HCC cells, indicating that the expression of CD147 might exist heterogeneity in different cancer cell types. Taken together, we identified HSPA12A as an activator of HCC migration, a role opposite to that of renal cancer cells. Inhibiting HSPA12A might be a potential therapeutic intervention for HCC metastasis.

Keywords: Heat shock protein A12A (HSPA12A); Hepatocellular carcinoma; Lactate export; Metastasis; Monocarboxylate transporter 4 (MCT4).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Hepatocellular* / metabolism
  • Cell Line, Tumor
  • Female
  • HSP70 Heat-Shock Proteins / metabolism*
  • Heat-Shock Proteins
  • Humans
  • Kidney Neoplasms*
  • Lactates
  • Liver Neoplasms* / metabolism
  • Male

Substances

  • HSP70 Heat-Shock Proteins
  • HSPA12A protein, human
  • Heat-Shock Proteins
  • Lactates