BEX2 is required for maintaining dormant cancer stem cell in hepatocellular carcinoma

Abstract

Cancer stem cells (CSCs) are responsible for therapy resistance and share several properties with normal stem cells. Here, we show that brain-expressed X-linked gene 2 (BEX2), which is essential for dormant CSCs in cholangiocarcinoma, is highly expressed in human hepatocellular carcinoma (HCC) lesions compared with the adjacent normal lesions and that in 41 HCC cases the BEX2 high expression group is correlated with a poor prognosis. BEX2 localizes to Ki67-negative (nonproliferative) cancer cells in HCC tissues and is highly expressed in the dormant fraction of HCC cell lines. Knockdown of BEX2 attenuates CSC phenotypes, including sphere formation ability and aldefluor activity, and BEX2 overexpression enhances these phenotypes.Moreover, BEX2 knockdown increases cisplatin sensitivity, and BEX2 expression is induced by cisplatin treatment. Taken together, these data suggest that BEX2 induces dormant CSC properties and affects the prognosis of patients with HCC.

Cancer Stem Cells and Their Vesicles, Together with Other Stem and Non-Stem Cells, Govern Critical Cancer Processes: Perspectives for Medical Development

“…A process regulated by a TME is the circadian clock ( Figure 2 ). The connection established here is due to the high degree of CSC property and its functional plasticity ( Table 1 ), which is dependent on the transition from slowly cycling quiescent phases to actively proliferating phenotypes [ 19 , 26 ]. Circadian clocks contribute to cancer growth by regulating stem cells and the TME.…”

“…In cancer tissue CSC concentrations occur within small volumes, the niches, analogous to the stromas of non-cancer cells [ 19 ]. Niches ( Figure 1 ) are the sites of high-degree CSC plasticity, which are dependent on transitions from slowly cycling quiescent phases to actively proliferating phenotypes, with intense secretion of their EVs [ 19 , 26 ]. Within niches, some of the general properties of stem cells and their vesicles depend on the cooperation of CSCs with MSCs [ 27 , 28 ].…”

Cancer Stem Cells in Intrahepatic Cholangiocarcinoma; Their Molecular Basis, and Therapeutic Implications

“…In cholangiocarcinoma, CD274 low (also known as PD-L1) cancer cells are dormant and possess high tumorigenicity ( Tamai et al, 2014 ). In CD274 low cells, brain expressed gene 2 ( BEX2 ) is highly expressed, and BEX2 high cells are dormant CSCs in iCCA and HCC ( Tamai et al, 2020 ; Fukushi et al, 2021 ). Knockdown of BEX2 induced a proliferating phase in the cell cycle in iCCA cell lines.…”

Cancer Stem Cells, Together with Mesenchymal Stem Cells and Other Cooperative Cells, Govern the Initiation and Development of Cancer

“…CSCs, identified a few years after 2000, account for significant fractions of the cells concentrated within cancer niches together with normal cancer cells, MSCs and various other collaborative, non-cancer cells, that participate in cancer functions (Figure 1). Functionally, however, the critical properties of CSCs are original [10][11][12][13]16,28,29]. Shared with MSCs can be other properties, such as broad proliferation capacity, signaling and expression of stem cell markers.…”

“…CSC concentrations were found to occur within small tissue volumes, the niches, analogous to the stromas of non-cancer cells [9,10]. Niches are the sites of high degree CSC plasticity dependent on transitions from slowly cycling quiescent phases to actively proliferative phenotypes [10][11][12]. Within niches, stem cells and their EVs are accompanied by other cells and their EVs: normal cancer cells, fibroblasts, immune (macrophages, lymphocytes) and other cells, all cooperative to cancer function (Figure 1) [12][13][14][15][16][17][18].…”