2022 Vol. 36, No. 4
It is difficult for physicians to identify patients with metastatic nasopharyngeal carcinoma (NPC) who are sensitive to local treatment of metastases. Here, we aimed to establish a prognostic model for survival and individualize treatments for patients with metastatic NPC. Data were collated from 240 NPC patients diagnosed with metachronous metastasis between 2006 and 2020 who received palliative chemotherapy with or without local treatment. Multivariable Cox regression was implemented to construct a nomogram which had a concordance index of 0.764 when predicting 1-, 3-, and 5-year overall survival (OS). We then classified patients according to risk, creating low- and high-risk groups using the nomogram. Differences in OS between the two groups were significant (P<0.001). In the low-risk group, the OS for patients who received local treatment was longer than those without (P=0.009). This novel nomogram shows good performance in classifying patients according to risk and may also be a promising tool for determining who responds best to local treatment. Further validation using external center data is warranted.
Mounting evidence indicates that long non-coding RNAs (lncRNAs) have critical roles in colorectal cancer (CRC) progression, providing many potential diagnostic biomarkers, prognostic biomarkers, and treatment targets. Here, we sought to investigate the role and underlying regulatory mechanism of lncRNA small nucleolar RNA host gene 16 (SNHG16) in CRC. The expressions of SNHG16 in CRC were identified by RNA-sequencing and quantitative reverse transcription PCR. The functions of SNHG16 were explored by a series of in vitro and in vivo assays (colony formation assay, flow cytometry assay, and xenograft model). Bioinformatics analysis, RNA fluorescence in situ hybridization and luciferase reporter assay were used to investigate the regulatory mechanism of effects of SNHG16. SNHG16 was found to be significantly elevated in human CRC tissues and cell lines. Functional studies suggested that SNHG16 promoted CRC cell growth both in vitro and in vivo. Mechanistically, we identified that SNHG16 is expressed predominantly in the cytoplasm. SNHG16 could interact with miR-214-3p and up-regulated its target ABCB1. This study indicated that SNHG16 plays an oncogenic role in CRC, suggesting it could be a novel biomarker and therapeutic target in CRC.
Genetic variants within or near the transcription factor 4 gene (TCF4) are robustly implicated in psychiatric disorders including schizophrenia. However, the biological pleiotropy poses considerable obstacles to dissect the potential relationship between TCF4 and those highly heterogeneous diseases. Through integrative transcriptomic analysis, we demonstrated that TCF4 is preferentially expressed in cortical interneurons during early brain development. Therefore, disruptions of interneuron development might be the underlying contribution of TCF4 perturbation to a range of neurodevelopmental disorders. Here, we performed chromatin immunoprecipitation sequencing (ChIP-seq) of TCF4 on human medial ganglionic eminence-like organoids (hMGEOs) to identify genome-wide TCF4 binding sites, followed by integration of multi-omics data from human fetal brain. We observed preferential expression of the isoform TCF4-B over TCF4-A. De novo motif analysis found that the identified 5916 TCF4 binding sites are significantly enriched for the E-box sequence. The predicted TCF4 targets in general have positively correlated expression levels with TCF4 in the cortical interneurons, and are primarily involved in biological processes related to neurogenesis. Interestingly, we found that TCF4 interacts with non-bHLH proteins such as FOS/JUN, which may underlie the functional specificity of TCF4 in hMGEOs. This study highlights the regulatory role of TCF4 in interneuron development and provides compelling evidence to support the biological rationale linking TCF4 to the developing cortical interneuron and psychiatric disorders.
2022, 36(4): 255-268. doi: 10.7555/JBR.36.20220072
Amyloids have traditionally been considered pathologic protein aggregates which contribute to neurodegeneration. New evidence however increasingly suggests that non-pathological amyloids are formed in animals during normal development. Amyloid-like aggregate formation was originally thought to be a conserved feature of animal gametogenesis. This hypothesis was based on findings which suggest that regulated amyloid formations govern yeast meiosis by way of meiosis-specific RNA binding proteins. Additional support came from studies which demonstrate that DAZL, a mammalian gametogenesis-specific RNA binding protein, also forms SDS-resistant aggregates in vivo. Here, we report evidence of aggregated BOULE formations, another DAZ family protein, during sperm development. Data suggest that in mouse testis, BOULE forms SDS-resistant amyloid-like aggregates. BOULE aggregate formation correlates with dynamic developmental expression during spermatogenesis but disappeared in Boule knockout testis. We also mapped essential small region in vitro BOULE aggregations, immediately downstream DAZ repeats, and found that aggregations positively correlated with temperature. We also performed enhanced UV cross-linking immunoprecipitation on BOULE aggregates from mouse testes and found that aggregates bind with a large number of spermatogenesis-related mRNAs. These findings provide insight into the amyloidogenic properties of gametogenesis-specific RNA binding proteins as a conserved feature in mammalian reproduction. Further investigation is warranted to understand the functional significance of BOULE amyloid-like formation during mouse spermatogenesis.
Microtubule-severing proteins (MTSPs), are a family of proteins which use adenosine triphosphate to sever microtubules. MTSPs have been shown to play an important role in multiple microtubule-involved cellular processes. One member of this family, fidgetin (FIGN), is also involved in male fertility; however, no studies have explored its roles in female fertility. In this study, we found mouse fidgetin is rich within oocyte zona pellucida (ZP) and is the only MTSP member to do so. Fidgetin also appears to interact with all three ZP proteins. These findings prompted us to propose that fidgetin might prevent polyspermy. Results from in vitro maturation oocytes analysis showed that fidgetin knockdown did cause polyspermy. We then deleted all three fidgetin isoforms with CRISPR/Cas9 technologies; however, female mice remained healthy and with normal fertility. Of all mouse MTSPs, only the mRNA level of fidgetin-like 1 (FIGNL1) significantly increased. Therefore, we assert that fidgetin-like 1 compensates fidgetin's roles in fidgetin knockout female mice.
Intrauterine adhesion (IUA) is a common clinical endometrial disease, which can severely damage the fertility and quality of life in women. This study aims to find the differentially expressed endogenous peptides and their possible roles in IUA. Liquid chromatography-mass spectrometry was used to identify the peptidomic profiling of IUA tissues, and the differentially expressed peptides were screened out. Using real-time quantitative PCR, Western blotting, and immunocytochemistry staining, the function of six endogenous peptides was verified in vitro. It was found that peptide 6 (T6) (peptide sequence: TFGGAPGFPLGSPLSSVFPR) could inhibit the expression of TGF-β1-induced cell fibrosis in human endometrial stromal cell line and primary human endometrial stromal cell at a concentration of 50 μmol/L. This study provides new targets for further clarifying the formation and prevention of IUA.