Increased resistin suggests poor prognosis and promotes development of lung adenocarcinoma

Abstract Background: Few oncogenic drivers of long noncoding RNAs (lncRNAs) have been identified and investigated. Identifying noncoding drivers provides potential strategies for novel interventions in lung adenocarcinoma (LUAD). Methods: We constructed a machine learning model for driver gene annotation using pan-cancer and clinical prognosis data from OncoKB and TCGA to predict potential oncogenic drivers of lncRNAs; then, we used zebrafish models to validate the biological function of candidate targets. The full length of FAM83H-AS1 was obtained by rapid amplification of the cDNA ends (RACE) assay. RNA pull-down, RNA immunoprecipitation (RIP), quantative mass spectrometry (QMS) and RNA sequencing (RNA-Seq) assays were utilized to explore the potential mechanisms. Additionally, we used CRISPR interference (CRISPRi) system and patient-derived tumor xenograft (PDTX) model to evaluate the therapeutic potential of targeting FAM83H-AS1 in vivo.Results: The results suggested that FAM83H-AS1 was a potential oncogenic driver from the chromosome 8q24 amplicon; increases in the expression of FAM83H-AS1 resulted in poor prognosis for LUAD patients both in JSCH and TCGA cohorts. Functional assays revealed that FAM83H-AS1 promotes malignant progression and inhibits apoptosis. Mechanistically, FAM83H-AS1 binds with HNRNPK to enhance the translation of oncogenes RAB8B and RAB14. Experiments using CRISPR interference (CRISPRi)-mediated xenografts and patient-derived tumor xenograft (PDTX) models indicated that targeting FAM83H-AS1 inhibited LUAD progression in vivo. Conclusions: Our work demonstrated that FAM83H-AS1 is a potential oncogenic driver that inhibits LUAD-mediated apoptosis via the FAM83H-AS1-HNRNPK-RAB8B/RAB14 axis. Importantly, we suggest targeting of FAM83H-AS1 as a potential therapeutic strategy for LUAD.

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MUC5AC enhances tumor heterogeneity in lung adenocarcinoma with mucin production and is associated with poor prognosis

Japanese Journal of Clinical Oncology ◽

10.1093/jjco/hyaa016 ◽

2020 ◽

Vol 50 (6) ◽

pp. 701-711

Author(s):

Yujie Dong ◽

Lijuan Zhou ◽

Dan Zhao ◽

Kun Li ◽

Zichen Liu ◽

...

Keyword(s):

Transcription Factor ◽

Lung Adenocarcinoma ◽

Poor Prognosis ◽

Egfr Mutations ◽

Driver Mutations ◽

Kras Mutations ◽

Mucin Production ◽

Thyroid Transcription Factor 1 ◽

Thyroid Transcription Factor ◽

Transcription Factor 1

Abstract Objective The clinicopathological significance of Mucin5AC (MUC5AC) in lung adenocarcinoma with mucin production is still unclear. This study aimed to explore MUC5AC expression in lung adenocarcinoma with mucin production and its correlation with histological subtypes, common driver mutations and its impact on prognosis. Methods MUC5AC and thyroid transcription factor 1 immunohistochemistry was performed on surgical samples from 90 patients with lung adenocarcinoma with mucin production. Common driver mutations including EGFR and KRAS mutations and ALK rearrangement were detected by established methods. Results MUC5AC was significantly associated with lymphovascular invasion (P = 0.023) and tumors with intra-cytoplasmic mucin (P < 0.001). Moreover, MUC5AC was more significant in invasive mucinous adenocarcinoma (P < 0.001), as well as in tumors with KRAS mutations (P = 0.005) and a lack of thyroid transcription factor 1 expression (P < 0.001). Conversely, MUC5AC was less significantly detected in acinar predominant adenocarcinoma (P = 0.036) and tumors with EGFR mutations (P = 0.001). Notably, MUC5AC in non-pure mucinous subtype of lung adenocarcinoma with mucin production showed more aggressive behavior, distinct expression pattern and a lack of significant correlation with thyroid transcription factor 1 (P = 0.113) when compared with pure mucinous subtype. MUC5AC-positive tumors were significantly associated with a worse prognosis compared to MUC5AC-negative tumors (P < 0.001). A multivariate survival analysis showed that MUC5AC was an independent prognosis factor for poor prognosis (P = 0.006). Conclusions The clinicopathological features of non-pure mucinous subtype of lung adenocarcinoma with mucin production were distinct and should be distinguished from pure mucinous subtype. MUC5AC was associated with poor prognosis and could be a potential therapeutic target for this distinct type of lung adenocarcinoma that has few effective treatments.

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