Lulu Yu

SRSF3 (SRp20) is an essential RNA splicing factor. By conditional knockout (KO) of Srsf3, we found Srsf3 at its physiological level plays a tumor-suppressive role in mouse liver carcinogenesis. Srsf3 KO in hepatocytes disrupted sex disparity in the development of DEN-induced liver cancer and resulted in high incidence of liver cancer in both male and female mice. In contrast, Srsf3 is oncogenic in the mouse mammary glands and Srsf3 KO significantly delayed the development of Erbb2 breast cancer. Srsf3 KO significantly increased the expression of transcription factors Sox4, E2f1, and Myc, calcium channel factor Trpv4, and zinc-binding Trim6 in liver cancer, but did not in Erbb2 breast cancer. Srsf3 KO enhanced the expression of glucose transmembrane transporter Mfsd4a and translation initiator Eif4a2 in DEN-induced liver cancer but reduced Mfsd4a and Eif4a2 expression in breast cancer. More importantly, Srsf3 KO reduced the expression of hepatocyte ERα and transcription factor Foxa family genes essential for sexual dimorphism in liver cancer and their downstream targets leukemia inhibitory factor receptor Lifr and epidermal growth factor receptor Egfr, but increased the expression of Myc. We further evidenced that SRSF3 binds to FOXA1 promoter and is responsible for FOXA1 promoter activity and FOXA1 expression in liver cancer cells. Together, our data highlight a functional paradigm of SRSF3 at its physiological level in tissue context-dependent gene regulation and in facilitating hepatocyte ERα and FOXA1 expression for sex disparity in liver cancer development.

Mouse papillomavirus (MmuPV1) is the first papillomavirus known to infect laboratory mice, making it an irreplaceable tool for research on papillomaviruses. Despite wide use, standardized techniques for conducting MmuPV1 animal research are lacking. In this report, we describe an unexpected MmuPV1 outbreak causing recurrent papillomatosis in a specific pathogen-free animal research facility. The infected mice displayed characteristic papillomatosis lesions from the muzzles, tails, and feet with histological signs including anisocytosis, epithelial dysplasia, and typical koilocytosis. Etiology studies showed that the papilloma tissues exhibited MmuPV1 infection with expression of viral early and late genes detected by RNA-ISH using MmuPV1 antisense probe to viral E6E7 region and antisense probe to viral L1 region. The viral L1 protein was detected by an anti-MmuPV1 L1 antibody. PCR amplification and cloning of the entire viral genome showed that the origin of the outbreak virus, named MmuPV1 Bethesda strain (GenBank Acc. No. PX123224), could be traced to the MmuPV1 virus previously used in studies at the same facility. Our data indicate that MmuPV1 could exist in a contaminated environment for a long period of time, and a standardized international animal protocol discussing how to handle MmuPV1 studies is urgently needed.

Increased expression of lnc-FANCI-2, a newly discovered long noncoding RNA, is associated with cervical lesion progression from cervical intraepithelial neoplasia stage 1 (CIN1, low grade), CIN2–3 (high grade), to cervical cancer. Viral oncoprotein E7 of high-risk human papillomaviruses (HR-HPVs) and host transcription factor YY1 are two major factors promoting lnc-FANCI-2 expression. Using CRISPR-Cas9 technology, we knocked out the expression of lnc-FANCI-2 in the HPV16-positive cervical cancer cell line, CaSki cells. The selected knockout (KO) single-cell clones displayed altered cell morphology and proliferation with changes of cellular soluble receptors, but normal HPV16 E6 and E7 expression. Relative to the parental cells, lnc-FANCI-2 KO cells exhibited significantly increased RAS signaling and epithelial-mesenchymal transition, but decreased response to IFN signaling, along with increased p-Akt and p-Erk1/2 (two RAS signaling effectors), IGFBP3, MCAM, VIM, and CCND2 (cyclin D2) and decreased expression of RAC3. lnc-FANCI-2 in CaSki interacts with cellular proteins H13, HNRH1, K1H1, MAP4K4, and RNPS1. MAP4K4 knockdown led to enhance the expression of p-Erk1/2 and p-Akt. High lnc-FANCI-2 and low MCAM levels in cervical cancer tissues were found to be associated with patients’ survival. A key function of lnc-FANCI-2 intrinsically regulates RAS signaling to impact cervical lesion progression and cervical cancer prognosis.

Objective To investigate the clinical significance of the inferior wall cartilage of the auditory meatus in surgical treatment of congenital first branchial cleft anomalies (CFBCAs) in children. Methods Twenty children diagnosed with CFBCAs who underwent surgery between December 2018 and June 2022 at our hospital were retrospectively analyzed and classified according to their Work lesion type. The guiding significance of the inferior wall cartilage in the surgical treatment of CFBCAs was summarized by investigating the adjacent relationships of the surgical lesions with the external auditory canal and facial nerve. Results Of the 20 patients, 16 were classified as Work type I and 4 as Work type II. The lesions were adjacent to the inferior wall cartilage of the auditory meatus in all children. Work type I lesions were located in the upper lateral aspect and were not adjacent to the facial nerve. Work type II lesions were located in the inferior-medial region of the facial nerve. The lesions were completely resected in all children. One patient experienced recurrence 3 months postoperatively because of a residual endochondral fistula. No patients developed facial paralysis or other complications. Conclusions The inferior wall cartilage of the auditory meatus may help to the identify the initial lesion of the CFBCAs and can be regarded as a guiding anatomical structure. These lesions can be completely resected. For resection of Work type II first branchial cleft lesions, the surgical incision can be narrower, and can be precisely positioned with the assistance of endoscope.

Human papillomaviruses (HPV) are a group of small non-enveloped DNA viruses whose infection causes benign tumors or cancers. HPV16 and HPV18, the two most common high-risk HPVs, are responsible for ~70% of all HPV-related cervical cancers and head and neck cancers. The expression of the HPV genome is highly dependent on cell differentiation and is strictly regulated at the transcriptional and post-transcriptional levels. Both HPV early and late transcripts differentially expressed in the infected cells are intron-containing bicistronic or polycistronic RNAs bearing more than one open reading frame (ORF), because of usage of alternative viral promoters and two alternative viral RNA polyadenylation signals. Papillomaviruses proficiently engage alternative RNA splicing to express individual ORFs from the bicistronic or polycistronic RNA transcripts. In this review, we discuss the genome structures and the updated transcription maps of HPV16 and HPV18, and the latest research advances in understanding RNA cis-elements, intron branch point sequences, and RNA-binding proteins in the regulation of viral RNA processing. Moreover, we briefly discuss the epigenetic modifications, including DNA methylation and possible APOBEC-mediated genome editing in HPV infections and carcinogenesis.

Integration of a virus genome into human chromosomal DNA is critical in viral carcinogenesis. In this report, we discovered that virus-host fusion transcripts are characteristically originated mainly from a single integration site in three cervical cancer cell lines, CaSki and SiHa cells with multiple HPV16 DNA integration sites and HeLa cells with multiple HPV18 DNA integration sites. The host genomic elements surrounding the integrated HPV genome are critical for efficient expression of the viral oncogenes. We found that HPV E6 and E7 are expressed by hijacking a host 3’ splice site and/or RNA polyadenylation signal for their production. The viral-host fusion transcripts may encode a chimeric viral-host fusion protein through alternative RNA splicing. One such E6* protein in SiHa cells was found to antagonize E6 function and knockdown of its expression further decreased p53 protein level and increased cell growth by promoting S phase entry. Together, our findings of the integrated virus genome expression only from a given integrated host genomic site will shed new light on possible application of precision medicine and the understanding of HPV carcinogenesis.

Objectives: Tangshan earthquake which had a magnitude of 7.8 killed approximately 250,000 people in China in 1976. In the present study, we sought to determine the prevalence and risks of mental disorders in adults who experienced earthquake as an infant or in the prenatal period.Methods: This cross‐sectional cohort study recruited participants based on the urban resident registry of Tangshan, Hebei province, 2013 using a multistage stratified cluster sampling method with selection probabilities proportional to size. We recruited subjects who were born between July 29, 1975 and April 28, 1978 that was one year before and 1.9 years after the occurrence of Tangshan Earthquake, respectively. Current psychiatric diagnoses and lifetime psychiatric diagnoses were obtained through the Structured Clinical Interview for DSM‐IV Axis I Disorders Patient Research Version. Unconditional logistic regression analysis was performed to analyze risk factors of mental disorders.Results: Totally1380 subjects were included with 392 subjects exposed to the earthquake in the fetal period, 399 subjects who experienced the earthquake during their infancy, and 589 subjects who had no exposure to the earthquake. Twenty‐one (2.7%; current 1.9%) subjects exposed to earthquake were diagnosed with major depressive disorderversus 2.3% (current 1.5%) in the non‐exposure group. Five (0.6%; current 0.6%) subjects with exposure to earthquake had bipolar disorder versus 0.9% in the non‐exposure group.Thirteen (1.6%; current 1.6%) subjects with exposure to earthquake had schizophreniaversus 0.2% in the non‐exposure group (P=0.006). Furthermore, 5.2% (current 3.7%) subjects with exposure to earthquake had anxiety disorders versus 5.7% (current 3.9%) in the non‐exposure group. Moreover, 8.1% (current 7.0%)subjects with exposure to earthquake had alcohol use disorders versus 7.1% (current 5.3%) in the non‐exposure group. Furthermore, the prevalence of schizophrenia of the prenatal exposure group (2.3%) was significantly higher than the other two groups (χ² = 10.273, P = 0.006); however, no statistically significant difference was found in the current and lifetime prevalence of other DSM‐IV axis I disorders among the three groups (P > 0.05). Our multivariate regression analysis showed that prenatal earthquake stress exposure was not a significant risk of any of the lifetime or current DSD‐IV axis I disorders.Conclusion: Adults who were exposed to earthquake in the prenatal period had a significantly higher rate of schizophrenia than those who were not exposed or who experienced earthquake in their infancy. No statistically significant difference was found in the current and lifetime prevalence of other DSM‐IV axis I disorders between those exposed and those not exposed to earthquake. Furthermore, prenatal earthquake stress exposure was not a significant risk of any of the lifetime or current DSD‐IV axis I disorders.