Dataset Information

Kupffer cell-derived IL6 promotes hepatocellular carcinoma metastasis via the JAK1-ACAP4 pathway

ABSTRACT: Tumor-associated macrophages (TAMs), which differentiate from tissue-resident macrophages, are recognized for their ability to influence cancer progression and metastasis. However, the specific role of Kupffer cells, the intrinsic macrophages of the liver, in the progression of hepatocellular carcinoma (HCC) remains unclear. In this study, we describe a novel mechanism by which exosomes derived from HCC cells induce Kupffer cells to transition into TAMs, thereby facilitating the metastasis of HCC in an IL6-JAK1-ACAP4 axis-dependent manner. Mechanistically, the exosome-mediated domestication of Kupffer cells by hepatoma cells constitutes one of the primary sources of IL6 production in the HCC microenvironment. IL6 then activates JAK1 to phosphorylate its downstream effector ACAP4 at Tyr843, a novel phosphorylation site identified in this context, which in turn promotes ARF6-GTPase activity and hepatoma cell migration. Furthermore, we found that the levels of IL6, as well as the phosphorylation of JAK1 and ACAP4 at Tyr843, were significantly greater in tumor tissues from HCC patients than in adjacent tissues. These findings suggest that the IL6-JAK1-ACAP4 axis may be a promising therapeutic target for HCC. Importantly, we screened bufalin, an active ingredient derived from natural products, and discovered that it inhibits JAK1 and disrupts the IL6-induced phosphorylation of ACAP4. This inhibition not only impairs hepatoma cell migration but also prevents the metastasis of HCC. These findings demonstrate the interplay between hepatoma cells and Kupffer cells through the IL6-JAK1-ACAP4 axis, thereby promoting HCC metastasis, and reveal the therapeutic potential of bufalin for the treatment of HCC through JAK1 inhibition.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Nan Li

LAB HEAD: Tao Li

PROVIDER: PXD057481 | Pride | 2025-05-26

REPOSITORIES: Pride

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Kupffer Cell-derived IL6 Promotes Hepatocellular Carcinoma Metastasis Via the JAK1-ACAP4 Pathway.

Li Tao T Song Xiaoyu X Chen Jiena J Li Yuan Y Lin Jie J Li Ping P Yu Simiao S Durojaye Olanrewaju Ayodeji OA Yang Fengrui F Liu Xing X Li Jian J Cheng Shiyuan S Yao Xuebiao X Ding Xia X

International journal of biological sciences 20250101 1

Tumor-associated macrophages (TAMs), which differentiate from tissue-resident macrophages, are recognized for their ability to influence cancer progression and metastasis. However, the specific role of Kupffer cells (KCs), the intrinsic macrophages of the liver, in the progression of hepatocellular carcinoma (HCC) remains unclear. In this study, we describe a novel mechanism by which exosomes derived from HCC cells induce KCs to transition into TAMs, thereby facilitating the metastasis of HCC in ...[more]

PMID: 39744421

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			Action	DRS
	EXO1.msf	Msf
	EXO1.msfView	Msf
	EXO1.pdResult	Other
	EXO1.pdResultView	Other
	EXO2.raw	Raw