2. Academic Validation
  3. NHE7 upregulation potentiates the uptake of small extracellular vesicles by enhancing maturation of macropinosomes in hepatocellular carcinoma

NHE7 upregulation potentiates the uptake of small extracellular vesicles by enhancing maturation of macropinosomes in hepatocellular carcinoma

  • Cancer Commun (Lond). 2023 Dec 28. doi: 10.1002/cac2.12515.
Yue Yao 1 2,  Yi Xu 1 3 4,  Liang Yu 1 3,  Ting-Mao Xue 1 5,  Zhi-Jie Xiao 6,  Pui-Chi Tin 1,  Hiu-Ling Fung 1,  Hoi-Tang Ma 1 7,  Jing-Ping Yun 8,  Judy Wai Ping Yam 1 7
Affiliations

Affiliations

  • 1 Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, P. R. China.
  • 2 Department of Endocrinology and Metabolism, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjing, P. R. China.
  • 3 Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjing, P. R. China.
  • 4 State Key Laboratory of Oncology in South China, Cancer Center of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.
  • 5 Department of Hepatobiliary Surgery II, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, P. R. China.
  • 6 Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, P. R. China.
  • 7 State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, P. R. China.
  • 8 Department of Pathology, Cancer Center of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.
PMID: 38152992 DOI: 10.1002/cac2.12515
Abstract

Background: Small extracellular vesicles (sEVs) mediate intercellular communication that contributes to hepatocellular carcinoma (HCC) progression via multifaceted pathways. The success of cell entry determines the effect of sEV on recipient cells. Here, we aimed to delineate the mechanisms underlying the uptake of sEV in HCC.

Methods: Macropinocytosis was examined by the ability of cells to internalize dextran and sEV. Macropinocytosis was analyzed in Na(+)/H(+) exchanger 7 (NHE7)-knockdown and -overexpressing cells. The properties of cells were studied using functional assays. pH biosensor was used to evaluate the intracellular and endosomal pH. The expression of NHE7 in patients' liver tissues was examined by immunofluorescent staining. Inducible silencing of NHE7 in established tumors was performed to reveal the therapeutic potential of targeting NHE7.

Results: The data revealed that macropinocytosis controlled the internalization of sEVs and their oncogenic effect on recipient cells. It was found that metastatic HCC cells exhibited the highest efficiency of sEV uptake relative to normal liver cells and non-metastatic HCC cells. Attenuation of macropinocytic activity by 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) limited the entry of sEVs and compromised cell aggressiveness. Mechanistically, we delineated that high level of NHE7, a sodium-hydrogen exchanger, alkalized intracellular pH and acidized endosomal pH, leading to the maturation of macropinosomes. Inducible inhibition of NHE7 in established tumors developed in mice delayed tumor development and suppressed lung metastasis. Clinically, NHE7 expression was upregulated and linked to dismal prognosis of HCC.

Conclusions: This study advances the understanding that NHE7 enhances sEV uptake by macropinocytosis to promote the malignant properties of HCC cells. Inhibition of sEV uptake via macropinocytosis can be exploited as a treatment alone or in combination with conventional therapeutic approaches for HCC.

Keywords

hepatocellular carcinoma; macropinocytosis; pH regulation; small extracellular vesicles; sodium-hydrogen exchanger.

Figures
Products