Background/Aims: Lung adenocarcinoma, a form of non-small cell lung cancer with high lethality at an advanced stage, is becoming more common in women, non- or never-smokers, and even young adults. At present, there are still no effective early diagnosis methods for patients to be cured in a timely manner. Circular RNAs (circRNAs), which are stable and conserved non-coding RNA in mammalian cells, have been reported to be widely involved in the processes of cancer disease. However, it is still a puzzle as to which specific circRNAs are involved in the development of early-stage lung adenocarcinoma. Methods: Tumor samples and paired adjacent normal tissues from 4 patients with early-stage lung adenocarcinoma were selected to investigate the expression profile of circRNAs by using a high-throughput circRNA microarray. Bioinformatic analyses were conducted to screen those differentially expressed circRNAs. qRT-PCR and sequencing were performed to assure the microarray data. Results: A total of 357 circRNAs were dysregulated in the tumor samples, which suggests potential roles in lung cancer. qRT-PCR detection showed that five selected circRNAs were identical to the microarray data, and the potential circRNA-miRNA interactions were predicted. Conclusion: This work illustrates that clusters of circRNAs are aberrantly expressed in early-stage lung adenocarcinoma, which might offer potential targets for the early diagnosis of this disease and new genetic insights into lung cancer.

The ubiquitin system, known as a common feature in eukaryotes, participates in multiple cellular processes, such as signal transduction, cell-cycle progression, receptor trafficking and endocytosis, and even the immune response. In lung cancer, evidence has revealed that aberrant events in ubiquitin-mediated processes can cause a variety of pathological outcomes including tumorigenesis and metastasis. Likewise, ubiquitination on the core components contributing to the activity of cell signaling controls bio-signal turnover and cell final destination. Given this, inhibitors targeting the ubiquitin system have been developed for lung cancer therapies and have shown great prospects for clinical application. However, the exact biological effects and physiological role of the drugs used in lung cancer therapies are still not clearly elucidated, which might seriously impede the progress of treatment. In this work, we summarize current research advances in cell signal regulation processes mediated through the ubiquitin system during the development of lung cancer, with the hope of improving the therapeutic effects by means of aiming at efficient targets.

Grb2 (Growth factor receptor-bound protein 2) is a key adaptor protein in maintaining the ERK activity via linking Sos1 (Son of sevenless homolog 1) or other proteins to activated RTKs, such as EGFR. Currently, little knowledge is available concerning the post-translational modification (PTM) of Grb2 except for its phosphorylation. Since emerging evidences have highlighted the importance of SUMOylation (Small ubiquitin-related modifier), a reversible PTM, in modulating protein functions, we wondered if Grb2 could be SUMOylated and thereby influences its functions especially involved in the Ras/MEK/ERK pathway. SUMOylation of Grb2 was analyzed with the in vivo SUMOylation assay using the Ni²⁺-NTA affinity pulldown and the in vitro E.coli-based SUMOylation assay. To test the ERK activity and cell transformation, the murine fibroblast cell line NIH/3T3 and the murine colon cancer cell line CMT-93 were used for the experiments including Grb2 knockdown, ectopic re-expression, cell transformation and migration. Immunoprecipitation (IP) was employed for seeking proteins that interact with SUMO modified Grb2. Xenograft tumor model in mice was conducted to verify that Grb2 SUMOylation regulated tumorigenesis in vivo. Grb2 can be SUMOylated by SUMO1 at lysine 56 (K⁵⁶), which is located in the linker region between the N-terminal SH3 domain and the SH2 domain. Knockdown of Grb2 reduced the ERK activity and suppressed cell motility and tumorigenesis in vitro and in vivo, which were all rescued by stable ectopic re-expression of wild-type Grb2 but not the mutant Grb2^K56R. Furthermore, Grb2 SUMOylation at K⁵⁶ increased the formation of Grb2-Sos1 complex, which sequentially leads to the activation of Ras/MEK/MAPK pathway. Our results provide evidences that Grb2 is SUMOylated in vivo and this modification enhances ERK activities via increasing the formation of Grb2-Sos1 complex, and may consequently promote cell motility, transformation and tumorigenesis.

Small RNA-induced gene silencing is essential for post-transcriptional regulation of gene expression; however, it remains unclear how miRNA/siRNA efficiency is regulated. Here we show that TARBP2 is SUMOylated at K52, which can be enhanced by its phosphorylation. This modification can stabilize TARBP2 via repressing its K⁴⁸-linked ubiquitination. We find that TARBP2 SUMOylation does not influence the overall production of mature miRNAs, but it regulates miRNA/siRNA efficiency. SUMOylated TARBP2 recruits Ago2 to constitute the RNA-induced silencing complex (RISC)-loading complex (RLC), and simultaneously promotes more pre-miRNAs to load into the RLC. Consequently, Ago2 is stabilized and miRNAs/siRNAs bound by TARBP2/Dicer is effectively transferred to Ago2. Thus, these processes lead to the formation of the effective RISC for RNA interference (RNAi). Collectively, our data suggest that SUMOylation of TARBP2 is required for regulating miRNA/siRNA efficiency, which is a general mechanism of miRNA/siRNA regulation.

Stress granules (SGs) are cytoplasmic, membraneless organelles that modulate mRNA metabolism and cellular adaptation under stress, yet the mechanisms by which they regulate cancer cell survival remain unclear. Here, we identify Poly(A)-Binding Protein Cytoplasmic 1 (PABPC1), a core SG component, as stress-inducible SUMOylation target. Upon various stress conditions, SUMOylated PABPC1 promotes SG assembly and enhances cancer cell survival. Transcriptome-wide analysis reveals that SUMOylated PABPC1 selectively stabilizes mRNAs enriched in conserved U-rich elements. Mechanistically, SUMOylated PABPC1 interacts with RNA-binding protein TIA1 to form PABPC1–SUMO–TIA1 complex that recruits U-rich mRNAs into SGs, protecting them from degradation. This process facilitates the expression of U-rich genes, such as mitophagy-related genes FUNDC1, BNIP3L, thereby maintaining cellular homeostasis and promoting cell survival under adverse conditions. Our findings reveal that PABPC1 SUMOylation connects stress granule assembly with selective U-rich mRNA stabilization and mitophagy, promoting cancer cell stress adaptation.

Objective: This study aims to reveal epidemiological features and trends of liver cancer (LC) in China.Methods: We retrieved data from the Global Burden of Disease database 2019. Joinpoint regression was used to examine the temporal trend of LC. Future trends of LC were estimated using the Nordpred.Results: The incidence, mortality, and disability-standardized life year (DALY) rate of LC declined in China from 1990 to 2019. Among >210,000 LC cases in 2019, the LC incidences were nearly 3.15 times higher in males than in females. LC cases and LC-associated deaths were mostly found among patients aged 65 to 69 years. The proportion of LC attributable to hepatitis B decreased over time, whereas the proportions of LC attributable to hepatitis C, alcohol use, and non-alcoholic steatohepatitis increased modestly from 1990 to 2019. The majority of LC-associated deaths could be traced to four risk factors: smoking (20%), drug use (13.6%), alcohol use (11.7%), and high body mass index (10.1%). Based on the Nordpred prediction, there will be a steady decline in the incidence (39.0%) and mortality (38.3%) of liver cancer over a 25-year period from 2020 to 2044.Conclusion: The disease burden of liver cancer in China has declined over the past 30 years. However, it remains important to control liver cancer among high-risk populations, especially elderly males with obesity, alcohol use, tobacco use, and/or drug abuse.