High Levels of DEAH-Box Helicases Relate to Poor Prognosis and Reduction of DHX9 Improves Radiosensitivity of Hepatocellular Carcinoma

Abstract

BackgroundLiver hepatocellular carcinoma (LIHC), one of the most common primary malignancies, exhibits high levels of molecular and clinical heterogeneity. Increasing evidence has confirmed the important roles of some RNA helicase families in tumor development, but the function of the DEAH-box RNA helicase family in LIHC therapeutic strategies has not yet been clarified.MethodsThe LIHC dataset was downloaded from The Cancer Genome Atlas (TCGA). Consensus clustering was applied to group the patients. Least absolute shrinkage and selection operator Cox regression and univariate and multivariate Cox regression were used to develop and validate a prognostic risk model. The Tumor Immune Estimation Resource and Tumor Immune Single Cell Hub databases were used to explore the role of DEAH-box RNA helicases in LIHC immunotherapy. In vitro experiments were performed to investigate the role of DHX9 in LIHC radiosensitivity.ResultsTwelve survival-related DEAH-box RNA helicases were identified. High helicase expression levels were associated with a poor prognosis and clinical features. A prognostic model comprising six DEAH-box RNA helicases (DHX8, DHX9, DHX34, DHX35, DHX38, and DHX57) was constructed. The risk score of this model was found to be an independent prognostic indicator, and LIHC patients with different prognosis were distinguished by the model in the training and test cohorts. DNA damage repair pathways were also enriched in patients with high-risk scores. The six DEAH-box RNA helicases in the risk model were substantially related to innate immune cell infiltration and immune inhibitors. In vitro experiments showed that DHX9 knockdown improved radiosensitivity by increasing DNA damage.ConclusionThe DEAH-box RNA helicase signature can be used as a reliable prognostic biomarker for LIHC. In addition, DHX9 may be a definitive indicator and therapeutic target in radiotherapy and immunotherapy for LIHC.

Comprehensive analysis of the role of pyroptosis-related genes in predicting prognosis in hepatocellular carcinoma

“…The landscape of mutations indicated that DHX9, NLRP3, and NLRP7 showed the highest frequency of mutations. Interestingly, previous study also found that DHX9 had a high expression level and ampli cation mutation frequency in HCC and was effective on DNA damage repair (27).…”

The enigmatic helicase DHX9 as a candidate prognostic biomarker for resected pancreatic ductal adenocarcinoma

“…DHX9, as an NTP-dependent helicase protein, plays a vital role in varieties of cellular processes, and aberrant DHX9 expression participates in multiple human diseases ( 14 , 15 ) including various cancers, e.g. colorectal cancer (CRC) ( 16 ), hepatocellular carcinoma ( 9 ), and prostate cancer ( 7 ). In a variety of clinical and translational studies, DHX9 was confirmed as a prognostic gene for cancers.…”

“…( 18 ) reported significant infiltrations of macrophages, dendritic cells, and neutrophils in gastric cancer patients with high DHX9 expression. In HCC, the six DEAH-box RNA helicases in the contrasted risk model were substantially associated with immune inhibitors and innate immune cell infiltrations ( 9 ). In addition, Jiao et al.…”

“…In cancers, DHX9 has been widely reported to promote proliferation, invasion, and metastasis of cancer cells and significantly correlated with poor prognosis, including prostate cancer ( 7 ), non-small-cell lung cancer (NSCLC) ( 8 ), and hepatocellular carcinoma (HCC) ( 9 ), which may function as epigenetic regulation of gene expression program ( 7 , 10 ) and influence in mRNA stability ( 11 ). In addition, DHX9 was also reported to interact with many transcription factors and influence signaling transformation ( 12 ).…”

Synthetic lethal interactions of DEAD/H-box helicases as targets for cancer therapy

“…The expression of DDX23 is enhanced in glioma tissues, and this is associated with poor survival of glioma patients ( 92 ). In computational analyses of 15 DEAH-box RNA helicases, elevated expression of 12 of them are associated with poor prognosis and worse clinical features in hepatocellular carcinoma ( 111 ). Because of their overarching role in RNA metabolism, DEAD/H-box helicases are likely to affect multiple aspects of cell behaviors, including cell proliferation, which may lead to cancer development.…”