Biology subjects

Tien, J.

Publications and source records attributed to Tien, J..

3 recordsLinked to original sources

bioRxiv2026

Dual-compartment engagement of STAR-family proteins SAM68 and QKI by LINC00941 sustains oncogenic fitness in RAS-driven lung cancer

Long non-coding RNAs (lncRNAs) are increasingly recognised as effectors of oncogenic signalling, yet the transcriptional programmes through which driver mutations regulate lncRNA expression remain poorly defined. Here we identify LINC00941 as a direct transcriptional target of FOSL1, an AP-1 transcription factor downstream of the KRAS-MAPK pathway, establishing the first FOSL1-regulated lncRNA in lung adenocarcinoma (LUAD). LINC00941 is significantly upregulated in LUAD across multiple independent cohorts, and its depletion via siRNAs, shRNAs, and antisense oligonucleotides (ASOs) induces proliferative arrest and stress-induced premature senescence, accompanied by transcriptomic suppression of cell cycle and DNA damage response (DDR) genes. Mechanistically, LINC00941 operates through a dual-compartment mechanism engaging two STAR-family RNA-binding proteins in distinct subcellular contexts. In the nucleus, LINC00941 binds SAM68 through its 700-1300 nucleotide region and shields it from proteasomemediated degradation, thereby sustaining SAM68-dependent PARP1 activation and DDR competency; RNF123 is identified as a candidate E3 ligase mediating SAM68 turnover in the absence of LINC00941. In the cytoplasm, LINC00941 sequesters QKI, preventing its nuclear translocation; LINC00941 depletion releases QKI to the nucleus, driving alternative splicing dysregulation including validated NUMB exon 12 exclusion, and QKI co-depletion rescues the anti-proliferative phenotype both in vitro and in xenograft models. Multi-cohort survival analysis across three independent LUAD datasets (n=649) identifies LINC00941 as an independent prognostic factor for poor overall survival. Gymnotic ASO-mediated targeting of LINC00941 significantly suppresses xenograft tumour growth without systemic toxicity, providing preclinical proof-of-concept for therapeutic tractability. Together, these findings establish LINC00941 as a compartment-specific oncogenic scaffold within the KRAS-FOSL1 transcriptional axis and a tractable therapeutic target in LUAD.

cancer biology↗

bioRxiv2024

Association of diet and inflammation with the vaginal microbiota of pregnant individuals with or without IBD

Background and aimsVaginal dysbiosis has been associated with adverse pregnancy outcomes. Here, we characterized the vaginal microbiota of pregnant individuals with inflammatory bowel disease (IBD) and investigated whether gut or vaginal inflammation and diet influence the vaginal microbiota diversity of these individuals. Study DesignWe recruited 48 individuals in their third trimester of pregnancy (IBD=23 and HC=18). We characterized the vaginal microbiota by 16S rRNA sequencing and the gut microbiota by shotgun sequencing. We measured fecal calprotectin in stool and pro-inflammatory cytokines in vaginal fluids. We determine dietary quality using validated 24-hour dietary recalls. ResultsPregnant individuals with IBD exhibit higher levels of fecal calprotectin and increased expression of Th17 pro-inflammatory cytokines (i.e., IL-6, IL-8, IL-17) in the vaginal mucosa compared to healthy pregnant individuals. High fecal calprotectin correlated with high vaginal microbiota diversity. Also, IL-4 (reduced in IBD) was associated with vaginal microbial composition. Regardless of IBD status, pregnant individuals with healthier diets and particularly optimal servings of vegetables and sugars exhibited a vaginal microbiota dominated by Lactobacillus crispatus, a species associated with a lower risk of preterm birth and bacterial vaginosis. ConclusionBesides gut inflammation, pregnant individuals with IBD also exhibit a Th17 immune tone in the vaginal mucosa. The vaginal microbiota diversity or composition, particularly high in the beneficial L. crispatus, is positively associated with healthier diets, regardless of IBD status. Why was the study conducted?An altered vaginal microbiota has been implicated in preterm birth. There is no research on the vaginal microbiome and the factors that influence it in pregnant individuals with Inflammatory Bowel Disease (IBD) at a higher risk of preterm delivery. Key findingsPregnant individuals with IBD exhibit a comparable vaginal microbiome to healthy pregnant individuals. However, pregnant individuals with IBD present a vaginal immune profile characterized by increased levels of Th17 pro-inflammatory cytokines. High dietary quality, and optimal consumption of vegetables and added sugars were associated with vaginal dominance by the beneficial L. crispatus. What does this add to what is known?Our results indicate that the vaginal immune environment and not the microbiome might explain poor pregnancy outcomes for individuals with IBD. Moreover, our study supports the importance of diet to favor L. crispatus, a bacterium associated with a lower risk of preterm birth.

microbiology↗

bioRxiv2017

An Essential Role for Argonaute 2 in EGFR-KRAS Signaling in Pancreatic Cancer Development

KRAS and EGFR are known essential mediators of pancreatic cancer development. In addition, KRAS and EGFR have both been shown to interact with and perturb the function of Argonaute 2 (AGO2), a key regulator of RNA-mediated gene silencing. Here, we employed a genetically engineered mouse model of pancreatic cancer to define the effects of conditional loss of AGO2 in KRASG12D-driven pancreatic cancer. Genetic ablation of AGO2 does not interfere with development of the normal pancreas or KRASG12D-driven early precursor pancreatic intraepithelial neoplasia (PanIN) lesions. Remarkably, however, AGO2 is required for progression from early to late PanIN lesions, development of pancreatic ductal adenocarcinoma (PDAC), and metastasis. AGO2 ablation permits PanIN initiation driven by the EGFR-RAS axis, but rather than progressing to PDAC, these lesions undergo profound oncogene-induced senescence (OIS). Loss of Trp53 (p53) in this model obviates the requirement of AGO2 for PDAC development. In mouse and human pancreatic tissues, increased expression of AGO2 and elevated co-localization with RAS at the plasma membrane is associated with PDAC progression. Furthermore, phosphorylation of AGO2Y393 by EGFR disrupts the interaction of wild-type RAS with AGO2 at the membrane, but does not affect the interaction of mutant KRAS with AGO2. ARS-1620, a G12C-specific inhibitor, disrupts the KRASG12C-AGO2 interaction specifically in pancreatic cancer cells harboring this mutant, demonstrating that the oncogenic KRAS-AGO2 interaction can be pharmacologically targeted. Taken together, our study supports a biphasic model of pancreatic cancer development: an AGO2-independent early phase of PanIN formation reliant on EGFR-RAS signaling, and an AGO2-dependent phase wherein the mutant KRAS-AGO2 interaction is critical to prevent OIS in PanINs and allow progression to PDAC.

cancer biology↗