AKR1C1 Activates STAT3 to Promote the Metastasis of Non-Small Cell Lung Cancer

Abstract

Metastasis is the leading cause of mortality for human non-small cell lung cancer (NSCLC). However, it is difficult to target tumor metastasis because the molecular mechanisms underlying NSCLC invasion and migration remain unclear. Methods: GEO data analyses and IHC analyses were performed to identify that the expression level of AKR1C1, a member of human aldo-keto reductase family, was highly elevated in patients with metastasis or metastatic foci of NSCLC patients. Functional analyses (in vitro and in vivo) and quantitative genomic analyses were preformed to confirm the pro-metastatic effects of AKR1C1 and the underlying mechanisms. The correlation of AKR1C1 with the prognosis of NSCLC patients was evaluated using Kaplan-Meier analyses. Results: in NSCLC patients, AKR1C1 expression was closely correlated with the metastatic potential of tumors. AKR1C1 overexpression in nonmetastatic cancer cells significantly promoted metastasis both in vitro and in vivo, whereas depletion of AKR1C1 in highly metastatic tumors potently alleviated these effects. Quantitative genomic and functional analyses revealed that AKR1C1 directly interacted with STAT3 and facilitated its phosphorylation—thus reinforcing the binding of STAT3 to the promoter regions of target genes—and then transactivated these genes, which ultimately promoted tumor metastasis. Further studies showed that AKR1C1 might facilitate the interaction of STAT3 with its upstream kinase JAK2. Intriguingly, AKR1C1 exerted these pro-metastatic effects in a catalytic-independent manner. In addition, a significant correlation between AKR1C1 and STAT3 pathway was observed in the metastatic foci of NSCLC patients, and the AKR1C1-STAT3 levels were highly correlated with a poor prognosis in NSCLC patients. Conclusions: taken together, we show that AKR1C1 is a potent inducer of NSCLC metastasis. Our study uncovers the active function of AKR1C1 as a key component of the STAT3 pathway, which promotes lung cancer metastasis, and highlights a candidate therapeutic target to potentially improve the survival of NSCLC patients with metastatic disease.

Identification and validation of AKR1C1/2/3 as hepatocellular carcinoma risk modules via an integrated strategy

“…Besides, AKR1C1/2/3 jointly acting as significant risk factors on prognosis was also validated in HCC patients. High expression of AKR1C1 was observed in many solid tumors and increasing studies have used AKR1C1 as a therapeutic target for treatment of cancers [3,23]. Our study firstly showed that AKR1C1 was also high-expressed in HCC tissues and high mRNA expression of AKR1C1 predicted poor OS and PFS.…”

Promoter Hypermethylation of CHODL Contributes to Carcinogenesis and Indicates Poor Survival in Patients with Early-stage Colorectal Cancer

“…Our RNA-Seq data suggested that some EMT-related genes (AKR1C1, CDH11, PCDH8, and CXCR2) were differentially expressed due to CHODL in CRC. AKR1C1, a member of the human aldo-keto reductase family, was downregulated according to our RNA-Seq analysis, and it exerts its prometastatic effects by directly interacting with STAT3, facilitating its phosphorylation and reinforcing STAT3 binding to the promoter regions of JAK2, which might promote metastasis in a catalytic-independent manner [29]. CDH11 is a mesenchymal cadherin that promotes cell migration by enhancing TGFβ-stimulated signaling [30].…”

Loss of AKR1C1 is a good prognostic factor in advanced NPC cases and increases chemosensitivity to cisplatin in NPC cells

“…These data implied that AKR1C1 was not a driver factor in the process of carcinogenesis and progression in NPC, AKR1C1 loss maybe an accompanying molecular event which contributed only to the chemotherapeutic sensitivity to cisplatin while not the malignant biological behaviours of NPC. Although AKR1C1 is reported to be involved in tumour metastasis through interaction with STAT3 in NSCLC 27 and to promote invasion of bladder cancer cells, evidence supporting the facilitation of metastasis is still lacking 17 . Taken together, the functional explorations of AKR1C1 provided a reasonable answer for the contradictory phenomenon between the expression data and the prognostic data in NPC.…”