Chromium (VI)-induced ALDH1A1/EGF axis promotes lung cancer progression.
Chromium (VI)-induced ALDH1A1/EGF axis promotes lung cancer progression.
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六价铬诱导的 ALDH1A1/EGF 轴促进肺癌进展
DOI：
10.1002/ctm2.1136
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发表时间：
2022-12
影响因子：
10.6
通讯作者：
中科院分区：
文献类型：
--
作者：
六价铬（Cr(VI)）在工业中广泛应用。六价铬暴露给公众健康带来沉重负担，从而增加了肺鳞状细胞癌（LUSC）的风险。六价铬诱导LUSC的潜在机制在很大程度上仍不清楚。在此，我们报道在六价铬转化的支气管上皮细胞（CrT）中，类似癌症干细胞（CSC）/肿瘤起始细胞（TIC）的亚群促进肺癌的肿瘤发生。从机制上讲，六价铬暴露通过KLF4介导的转录特异性地提高了醛脱氢酶1A1（ALDH1A1，一种癌症干细胞标志物）的表达水平。ALDH1A1维持CrT/TICs的自我更新，并促进CrT/TICs中表皮生长因子（EGF）的表达和分泌，这随后促进了分化癌细胞中表皮生长因子受体（EGFR）信号的激活以及LUSC肿瘤的生长。此外，ALDH1A1抑制剂A37和吉西他滨协同抑制LUSC的进展。重要的是，ALDH1A1高表达水平与临床晚期呈正相关，并预示LUSC患者预后不良。这些发现阐明了ALDH1A1如何调节TICs的EGF分泌以促进LUSC肿瘤发生，突出了恶性肺癌的新治疗策略。
由ALDH1A1维持的CrT/TICs在六价铬诱导的细胞恶性转化中驱动肺癌肿瘤发生。
六价铬暴露通过KLF4介导的转录特异性诱导ALDH1A1表达。
KLF4/ALDH1A1调节轴通过促进CrT/TICs中EGF的表达和分泌来促进分化癌细胞和LUSC肿瘤生长。
ALDH1A1抑制剂A37使LUSC对吉西他滨治疗敏感。
Cr(VI) is broadly applied in industry. Cr(VI) exposure places a big burden on public health, thereby increasing the risk of lung squamous cell carcinoma (LUSC). The mechanisms underlying Cr(VI)‐induced LUSC remain largely elusive. Here, we report that the cancer stem cell (CSC)/tumour‐initiating cell (TIC)‐like subgroup within Cr(VI)‐transformed bronchial epithelial cells (CrT) promotes lung cancer tumourigenesis. Mechanistically, Cr(VI) exposure specifically increases the expression levels of aldehyde dehydrogenase 1A1 (ALDH1A1), a CSC marker, through KLF4‐mediated transcription. ALDH1A1 maintains self‐renewal of CrT/TICs and facilitates the expression and secretion of EGF from CrT/TICs, which subsequently promotes the activation of EGFR signalling in differentiated cancer cells and tumour growth of LUSC. In addition, the ALDH1A1 inhibitor A37 and gemcitabine synergistically suppress LUSC progression. Importantly, high ALDH1A1 expression levels are positively correlated with advanced clinical stages and predict poor survival in LUSC patients. These findings elucidate how ALDH1A1 modulates EGF secretion from TICs to facilitate LUSC tumourigenesis, highlighting new therapeutic strategies for malignant lung cancers. CrT/TICs maintained by ALDH1A1 drive lung cancer tumourigenesis within Cr (VI)‐induced cellular malignant transformation. Cr(VI)‐exposure specifically induces ALDH1A1 expression via KLF4‐mediated transcription. KLF4/ALDH1A1 regulatory axis promotes differentiated cancer cells and tumour growth of LUSC by facilitating EGF expression and secretion from CrT/TICs. A37, the ALDH1A1 inhibitor, sensitises LUSC to gemcitabine treatment.
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影响因子：
10.4
作者：
Beaver LM;Stemmy EJ;Schwartz AM;Damsker JM;Constant SL;Ceryak SM;Patierno SR
通讯作者：
Patierno SR
影响因子：
11.2
作者：
Schultz MJ;Holdbrooks AT;Chakraborty A;Grizzle WE;Landen CN;Buchsbaum DJ;Conner MG;Arend RC;Yoon KJ;Klug CA;Bullard DC;Kesterson RA;Oliver PG;O'Connor AK;Yoder BK;Bellis SL
通讯作者：
Bellis SL
影响因子：
64.5
作者：
Takahashi, Kazutoshi;Yamanaka, Shinya
通讯作者：
Yamanaka, Shinya
DOI：
10.1158/1541-7786.mcr-08-0393
发表时间：
2009-03
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Jiang F;Qiu Q;Khanna A;Todd NW;Deepak J;Xing L;Wang H;Liu Z;Su Y;Stass SA;Katz RL
通讯作者：
Katz RL
影响因子：
4.6
作者：
Ghyselinck, Norbert B.;Duester, Gregg
通讯作者：
Duester, Gregg