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Chromium (VI)-induced ALDH1A1/EGF axis promotes lung cancer progression.

ABSTRACT: 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.

SUBMITTER: Ge X

PROVIDER: S-EPMC9742488 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Chromium (VI)-induced ALDH1A1/EGF axis promotes lung cancer progression.

Ge Xin X Li Mengdie M Song Guo-Xin GX Zhang Zhixiang Z Yin Jianxing J Ge Zehe Z Shi Zhumei Z Liu Ling-Zhi LZ Jiang Bing-Hua BH Qian Xu X Shen Hua H

Clinical and translational medicine 20221201 12

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 a ...[more]

PMID: 36504325

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Project description:BackgroundNon-small cell lung cancer (NSCLC) is the leading cause of cancer death, necessitating the identification of novel therapeutic targets. P21-activated kinases-1 (PAK1) plays a crucial role in oncogenesis, including NSCLC. Recent findings have elucidated T cell factor 1 (TCF1) as an anti-tumour factor, influencing T cell biology. However, the precise mechanism by which PAK1 promotes NSCLC progression via TCF1 regulation remains unclear.MethodsWe collected 23 pairs of NSCLC tissue samples and obtained NSCLC RNA sequencing data and corresponding clinicopathologic information from The Cancer Genome Atlas (TCGA). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) assessed PAK1 and TCF1 expression in NSCLC tissues and cells. Gain and loss-of-function experiments evaluated PAK1 and TCF1 effects on cell proliferation, invasion, migration, and apoptosis in vitro. Mechanistically, western blot (WB) and immunoprecipitation analysis evaluated the interaction between PAK1 and TCF1 in NSCLC. Finally, we assessed the clinical prognostic, disease progression, and immunotherapy response of PAK1 and TCF1 and their correlation with immune cell infiltration, immune checkpoint inhibitors (PD1, PDL1).ResultsPAK1 expression was elevated in NSCLC tissues and cells, while TCF1 was significantly downregulated. PAK1 expression showed a significant inverse correlation with TCF1 mRNA in NSCLC. Silencing PAK1 (using shRNAs) and inhibiting PAK1 with the small molecule IPA-3 suppressed NSCLC cell malignancy in a dose-dependent manner, upregulating TCF1 expression, and vice versa. TCF1 amplification with the small molecule (TWS119) inhibited NSCLC cell proliferation, migration, and invasion in a dose-dependent manner without affecting PAK1 expression. Immunoprecipitation analysis confirmed PAK1 and TCF1 interaction in NSCLC. Joint survival analysis indicated that high PAK1 and low TCF1 expression were associated with unfavourable survival in patients with NSCLC. Lastly, the TCF1 was significantly correlated with immune cell infiltration [CD8+ T cell, and tumor infiltrating lymphocytes (TILs)], immune checkpoint inhibitors (PD1, PDL1), and can accurately predict the immunotherapeutic response.ConclusionThis study demonstrates, for the first time, that PAK1 negatively regulates TCF1, contributing to NSCLC pathogenesis. The PAK1/TCF1 regulatory axis emerges as a critical determinant of carcinogenesis and a promising therapeutic target for NSCLC.

Project description:Long non-coding RNAs (lncRNAs) serve important regulatory roles in human tumors. The aim of the present study was to examine the role of ribonuclease P RNA component H1 (RPPH1) in non-small cell lung cancer (NSCLC). RPPH1 expression was assessed in datasets from The Cancer Genome Atlas, as well as lung cancer cell lines and patients with NSCLC. RPPH1 was significantly upregulated in NSCLC cell lines, compared with a normal lung epithelial cell line. Moreover, high RPPH1 expression was associated with poor overall survival and disease progression. RPPH1 was knocked down in A549 and H1299 cells using short hairpin (sh) RNA constructs, and the expressions of target genes and proteins were determined by reverse transcription-quantitative PCR and western blotting. Cell invasion potential was also determined using Transwell Matrigel assays. Compared with the negative control, RPPH1 silencing significantly reduced the number of invading cells, increased E-cadherin expression and reduced vimentin protein expression. Cell resistance to cisplatin/cis-diamminedichloridoplatinum (CDDP) was also evaluated using Cell Counting Kit-8 and colony formation assays. RPPH1 overexpression increased the resistance of A549 and H1299 cells to CDDP. Moreover, the potential interactions between RPPH1, microRNA (miR)-326 and Wnt family member 2B (WNT2B) were investigated using luciferase reporter assays and co-transfection experiments. MiR-326 expression was directly inhibited by RPPH1. In A549 cells co-transfected with shRPPH1 and miR-326 inhibitor, the invading cell number significantly increased compared with cells transfected with shRPPH1 alone. In addition, E-cadherin expression levels were reduced, and vimentin was upregulated. MiR-326 overexpression partially reduced the resistance of A549 cells to CDDP induced by RPPH1 overexpression. WNT2B expression was directly suppressed using miR-326. A549 cells co-transfected with a miR-326 mimic and a WNT2B overexpression vector demonstrated increased invasion potential, reduced E-cadherin and increased vimentin protein expression levels, compared with cells transfected with the mimic alone. miR-326 overexpression reduced CDDP resistance in A549 cells. However, co-transfection with WNT2B partially enhanced CDDP resistance, compared with the mimic alone. In conclusion, RPPH1 promoted NSCLC progression and lung cancer cell resistance to CDDP through miR-326 and WNT2B.

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Chromium (VI)-induced ALDH1A1/EGF axis promotes lung cancer progression.

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Chromium (VI)-induced ALDH1A1/EGF axis promotes lung cancer progression.

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