Lung cancer is an extremely aggressive malignancy and a leading cause of cancer-related death worldwide. LC can be divided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SSCLC), of which non-small cell lung cancer (NSCLC) accounts for the majority, and lung adenocarcinoma (LUAD) is the most common pathological subtype.
Despite great advances in the diagnosis and clinical treatment of LUAD, 5-year survival remains low due to difficulty in early detection, high rate of metastasis, resistance to chemoradiation, and lack of systemic therapy. Therefore, the insight into the molecular mechanisms of LUAD development and the search for new molecular markers are important to improve the diagnostic and therapeutic level of LUAD.
Recently, researchers from Zhengzhou University published "HNRNPK / CLCN3 axis facilitates the progression of LUAD through CAF-tumor interaction" in the journal International Journal of Biological Sciences, which revealed that the HNRNPK / CLCN 3 axis promotes the progression of LUAD through the CAF-tumor interaction.
Chloride channel 3 (CLCN 3) is regulated by transcriptional coactivators, but it is still unclear which core transcription factor regulates CLCN 3. The role of CLCN 3 in lung adenocarcinoma (LUAD) is still unknown, and the relationship with the tumor microenvironment is still unclear. The investigator down-regulated promoter-binding transcription factors with a 5 ′ -biotin-labeled CLCN 3 promoter probe. The mechanisms were further investigated using LUAD samples, cell lines, and xenograft mouse models.
CLCN 3 is upregulated in human LUAD, and CLCN 3 gene knockout suppresses tumor proliferation and migration in vitro. Next, the heterogeneous nuclear ribonucleoprotein K (HNRNPK) was confirmed for the first time as a CLCN 3 promoter-binding transcription factor. Mechanistically, HNRNPK knockout inhibited the promoter activity of CLCN 3, thereby regulating CLCN 3 expression at the transcriptional level and identified the binding motif 'GCGAGG' and the binding site '-538 / -248BP'.
Subsequently, RNA-seq data indicated that the main function of HNRNPK is similar to CLCN 3. The in vitro and in vivo results indicate that CLCN 3 expression and function are regulated by HNRNPK. By isolating primary tumor-associated fibroblasts (CAF) from human LUAD, the investigators demonstrated that reduced extracellular CLCN 3 secretion caused by HNRNPK knockout inhibited the activation of CAF and the production of transforming growth factor- β 1, thus feedback inhibiting nuclear HNRNPK expression and LUAD progression.
Furthermore, this phenomenon was rescued after the addition of the transforming growth factor-CLCN 1, revealing that the HNRNPK / β axis promotes the progression of LUAD through the cell-to-cell interactions. Finally, the investigators found that CLCN 3 and HNRNPK are upregulated in LUAD patients, and are associated with a poor prognosis.
In this work, the focus was on determining the changes in the expression of the HNRNPK / CLCN 3 axis in LUAD cells. Given that the main function and prognostic roles of HNRNPK are the same as CLCN 3, the investigators suggest that HNRNPK and CLCN 3 play equally important roles in the progression of LUAD, and that the therapeutic potential of targeting HNRNPK and targeting CLCN 3 may be the same.
In this study, the investigators have provided a schematic diagram of the relationship between CLCN 3 and HNRNPK in LUAD. First, CLCN 3 is upregulated in human LUAD and promotes tumor proliferation and migration. Second, we verified that HNRNPK is a CLCN 3 promoter-binding transcription factor and identified its binding motif 'GCGAGG' and the binding site '-538 / -248BP'. HNRNPK: Both regulate the expression and CLCN 3 function in vitro and in vivo, and the HNRNPK-CLCN 3 axis promotes the progression of LUAD through CAF – tumor interaction feedback.
