The BAFF/NFκB axis is crucial to interactions between sorafenib-resistant HCC cells and cancer-associated fibroblasts.
The BAFF/NFκB axis is crucial to interactions between sorafenib-resistant HCC cells and cancer-associated fibroblasts.
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DOI：
10.1111/cas.15041
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发表时间：
2021-09
期刊：
影响因子：
5.7
通讯作者：
Shimada M
中科院分区：
文献类型：
--
作者：
Gao L;Morine Y;Yamada S;Saito Y;Ikemoto T;Tokuda K;Miyazaki K;Okikawa S;Takasu C;Shimada M
肿瘤微环境影响肝细胞癌（HCC）细胞的恶性程度，而癌相关成纤维细胞（CAF）在微环境中起着重要作用。由于最近的研究表明从化学抗性和非抗性癌症组织中分离的CAF之间存在差异，因此我们研究了耐药HCC共培养CAF的细胞内机制以及这些CAF与癌细胞之间的相互作用。我们建立了索拉非尼耐药（SR）Huh 7（人HCC）细胞系，并通过细胞因子测定对其进行了表征，然后通过将人肝星状细胞与耐药或亲本Huh 7细胞共培养来开发CAF。将2种类型的CAF与亲本Huh 7细胞共培养，然后在索拉非尼处理下检查这些Huh 7细胞的细胞活力。SR Huh 7（Huh 7 SR）细胞表达增加的B-细胞活化因子（BAFF），这促进了Huh 7 SR-共培养的CAF中CAF特异性标志物的高表达，显示出活化的BAFF、BAFF-R和NFκB-Nrf 2通路下游，并加重了共培养的Huh 7细胞的侵袭、迁移和耐药性。当我们敲低Huh 7 SR细胞中的BAFF表达时，先前在Huh 7 SR-共培养的CAFs中增加的恶性度和BAFF/NFκB轴逆转，并且在共培养的Huh 7细胞中增强的化学抗性也恢复。总之，BAFF/NFκB通路在与来自耐药Huh 7的细胞培养基共培养的CAF中被激活，这促进了化学抗性，并增加了共培养的非耐药Huh 7细胞的恶性度。这表明CAF中的BAFF/NFκB轴可能是肝癌化疗耐药的潜在治疗靶点。在这项研究中，我们建立了索拉非尼耐药（SR）Huh 7（人肝细胞癌[HCC]）细胞系，并从耐药或亲本Huh 7细胞诱导产生了癌症相关成纤维细胞（CAF）。我们发现，B-细胞活化因子（BAFF）-NFκB通路在索拉非尼B-耐药Huh 7-共培养的CAFs中被激活，这促进了共培养的非耐药Huh 7细胞的化疗耐药性并增加了恶性程度。提示BAFF‐NFκB轴在SR HCC与CAFs的相互作用中起着重要作用，可能是导致HCC化疗耐药的CAFs的潜在治疗靶点。
The tumor microenvironment affects malignancy in hepatocellular carcinoma (HCC) cells, and cancer‐associated fibroblasts (CAFs) play an important role in the microenvironment. As recent studies indicated a difference between CAFs isolated from chemoresistant and non‐resistant cancer tissues, therefore we investigated the intracellular mechanism in resistant HCC co‐cultured CAFs and interactions between these CAFs with cancer cells. We established a sorafenib‐resistant (SR) Huh7 (human HCC) cell line, and characterized it with cytokine assays, then developed CAFs by co‐culturing human hepatic stellate cells with resistant or parental Huh7 cells. The 2 types of CAFs were co‐cultured with parental Huh7 cells, thereafter the cell viability of these Huh7 cells was checked under sorafenib treatment. The SR Huh7 (Huh7SR) cells expressed increased B‐cell activating factor (BAFF), which promoted high expression of CAF‐specific markers in Huh7SR‐co‐cultured CAFs, showed activated BAFF, BAFF‐R, and downstream of the NFκB‐Nrf2 pathway, and aggravated invasion, migration, and drug resistance in co‐cultured Huh7 cells. When we knocked down BAFF expression in Huh7SR cells, the previously increased malignancy and BAFF/NFκB axis in Huh7SR‐co‐cultured CAFs reversed, and enhanced chemoresistance in co‐cultured Huh7 cells returned as well. In conclusion, the BAFF/NFκB pathway was activated in CAFs co‐cultured with cell‐culture medium from resistant Huh7, which promoted chemoresistance, and increased the malignancy in co‐cultured non‐resistant Huh7 cells. This suggests that the BAFF/NFκB axis in CAFs might be a potential therapeutic target in chemoresistance of HCC. In this study, we established a sorafenib‐resistant (SR) Huh7 (human hepatocellular carcinoma [HCC]) cell line, and developed cancer‐associated fibroblasts (CAFs) induced from resistant or parental Huh7 cells. We found that the B‐cell activating factor (BAFF)‐NFκB pathway was activated in sorafenib‐resistant Huh7‐co‐cultured CAFs, which promoted chemoresistance and increased malignancy in co‐cultured non‐resistant Huh7 cells. This suggests that the BAFF‐NFκB axis plays a crucial role between the interaction of SR HCC and CAFs, and it might be a potential therapeutic target in CAFs that caused chemoresistance of HCC.
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影响因子：
3.8
作者：
Pelekanou V;Kampa M;Kafousi M;Darivianaki K;Sanidas E;Tsiftsis DD;Stathopoulos EN;Tsapis A;Castanas E
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Castanas E
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10.1016/j.bbrc.2017.02.128
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2017-04-29
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13
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影响因子：
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