SRSF3-mediated Ki67 exon 7 alternative splicing regulates Head and Neck Squamous Cell Carcinoma progression via AKR1C2
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE213022 | GEO | 2023/02/23
REPOSITORIES: GEO
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Project description:Ki67 is a well-known proliferation marker with a large size of around 350 kDa, but its biological function remains largely unknown. The roles of Ki67 in tumor prognosis are still controversial. Ki67 has two isoforms generated by alternative splicing of exon 7. The roles and regulatory mechanisms of Ki67 isoforms in tumor progression are not clear. In the present study, we surprisingly find that the increased inclusion of Ki67 exon 7, not total Ki67 expression level, was significantly associated with poor prognosis in multiple cancer types, including head and neck squamous cell carcinoma (HNSCC). Importantly, the Ki67 exon 7-included isoform is required for HNSCC cell proliferation, cell cycle progression, cell migration, and tumorigenesis. Unexpectedly, Ki67 exon 7-included isoform is positively associated with intracellular reactive oxygen species (ROS) level. Mechanically, splicing factor SRSF3 could promote exon 7 inclusion via its two exonic splicing enhancers. RNA-seq revealed that aldo-keto reductase AKR1C2 is a novel tumor-suppressive gene targeted by Ki67 exon 7-included isoform in HNSCC cells. Our study illuminates that the inclusion of Ki67 exon 7 has important prognostic value in cancers and is essential for tumorigenesis. Our study also suggested a new SRSF3/Ki67/AKR1C2 regulatory axis during HNSCC tumor progression.
| S-EPMC9959251 | biostudies-literature
Project description:SRSF3-mediated Ki67 exon 7 alternative splicing regulates Head and Neck Squamous Cell Carcinoma progression via AKR1C2
| PRJNA878796 | ENA
Project description:B and T cells can recognise and respond to a vast array of foreign pathogens by virtue of the diverse antigen-receptor repertoire generated by gene rearrangement during development. Here, we show that deficiency in Ki67, a nuclear protein ubiquitously expressed throughout the cell cycle, impairs B-cell development at specific, early stages. We identified that Ki67 maintains global chromatin accessibility in lymphocyte progenitors at stages where antigen-receptor gene rearrangements occur and that gene rearrangement is less efficient in the absence of Ki67. That the defects in B cell development are caused by disrupted antigen-receptor gene rearrangement is shown by pre-rearranged antigen-receptor genes fully compensating for loss of Ki67. Collectively, these results identify a unique contribution from Ki67 to somatic antigen-receptor gene rearrangement.
2024-05-31 | GSE246986 | GEO
Project description:Ki67 is a widely-used proliferation marker with functions in chromosomal organization. It forms a protective layer around mitotic chromosomes and is involved in genome positioning in interphase. However, a detailed understanding of how Ki67 organizes the genome was still lacking, partially because genome-wide interaction profiles were missing. Here, we generate DNA-Ki67 interaction profiles using our pA-DamID method, and show that Ki67 interacts with the genome in a domain-like pattern that partially overlaps with lamina-associated domains.
2021-10-20 | GSE186206 | GEO
Project description:Intervention1: Immunohistochemistry: Application of Immunohistochemical markers like Her2 and Ki67 on paraffin blocks of resected specimen of colorectal carcinoma patients for the duration or till the desired sample size is achieved, whichever is earlier.
Control Intervention1: NIL: NIL
Primary outcome(s): Prognostication of Her2 and Ki67 in colorectal Carcinoma patients.Timepoint: Primary outcome is expected to be achieved by the end of 2 years.
Study Design: Other Method of generating randomization sequence: Method of allocation concealment: Blinding and masking:
| 76675 | ecrin-mdr-crc
Project description:Background: Breast cancer patients present lower 1,25(OH)2D3 or 25(OH)D3 serum levels than unaffected women. Although 1,25(OH)2D3 pharmacological concentrations of 1,25(OH)2D3 may exert antiproliferative effects in breast cancer cell lines, much uncertainty remains about the effects of calcitriol supplementation in tumor specimens in vivo. We have evaluated tumor dimension (ultrassonography), proliferative index (Ki67 expression), 25(OH)D3 serum concentration and gene expression profile, before and after a short term calcitriol supplementation (dose to prevent osteoporosis) to post-menopausal patients. Results: Thirty three patients with operable disease had tumor samples evaluated. Most of them (87.5%) presented 25(OH)D3 insufficiency (<30 ng/mL). Median period of calcitriol supplementation was 30 days. Although tumor dimension did not vary, Ki67 immunoexpression decreased after supplementation. Transcriptional analysis of 15 matched pre/post-supplementation samples using U133 Plus 2.0 GeneChip (Affymetrix) revealed 18 genes over-expressed in post-supplementation tumors. As a technical validation procedure, expression of four genes was also determined by RT-qPCR and a direct correlation was observed between both methods (microarray vs PCR). To further explore the effects of near physiological concentrations of calcitriol on breast cancer samples, an ex vivo model of fresh tumor slices was utilized. Tumor samples from another 12 post-menopausal patients were sliced and treated in vitro with slightly high concentrations of calcitriol (0.5nM), that can be attained in vivo, for 24 hours In this model, expression of PBEF1, EGR1, ATF3, FOS and RGS1 was not induced after a short exposure to calcitriol. Conclusions: In our work, most post-menopausal breast cancer patients presented at least 25(OH)D3 insufficiency. In these patients, a short period of calcitriol supplementation may prevent tumor growth and reduce Ki67 expression, probably associated with discrete transcriptional changes. This observation deserves further investigation to better clarify calcitriol effects in tumor behavior under physiological conditions. Post-menopausal patients with early stage breast cancer, in the absence of distant metastasis, were invited to take part in the study. This protocol was approved by the Institutional Ethics Committee, and a written informed consent was signed by all participants. Patients had blood and tumor samples collected during biopsy, and were prescribed calcitriol supplementation, (Rocaltrol)TM 0.50 g/day PO, as recommended for osteoporosis prevention. Tumor specimens obtained during biopsy (pre-supplementation) or breast surgery (post-supplementation) were hand dissected and samples with at least 70% tumor cells were further processed. Breast surgery followed in about one month
2012-02-18 | E-GEOD-35925 | biostudies-arrayexpress
Project description:Background and objectivesAlternative splicing is increasingly associated with cancers. HnRNP L is a splicing factor that promotes carcinogenesis in head and neck squamous cell carcinoma (HNSCC) and other cancers. Alternative exon 7 of hnRNP L contains an in-frame stop codon. Exon 7-included transcripts can be degraded via nonsense-mediated decay or encode a truncated hnRNP L protein. Exon 7-excluded transcripts can encode full-length functional hnRNP L protein. HnRNP L has an autoregulation mechanism by promoting the inclusion of its own exon 7. This study aimed to understand the relationship between the alternative splicing of exon 7 and HNSCC. Oncogenic splicing factor SRSF3 has an alternative exon 4 and similar autoregulation mechanism. HnRNP L promotes SRSF3 exon 4 inclusion and then inhibits SRSF3 autoregulation.Materials and methodsThe relationship between alternative splicing of hnRNP L exon 7 and clinical characteristics of HNSCC in a TCGA dataset was analyzed and confirmed by RT-PCR in a cohort of 61 oral squamous cell carcinoma (OSCC) patients. The regulators of exon 7 splicing were screened in 29 splicing factors and confirmed by overexpression or silencing assay in HEK 293, CAL 27, and SCC-9 cell lines.ResultsThe inclusion of hnRNP L exon 7 was significantly negatively associated with the progression and prognosis of HNSCC, which was confirmed in the cohort of 61 OSCC patients. SRSF3 inhibited exon 7 inclusion and hnRNP L autoregulation and then promoted the expression of full-length functional hnRNP L protein. SRSF3 exon 4 inclusion was correlated with hnRNP L exon 7 inclusion in both HNSCC and breast cancer. HNSCC patients with both low hnRNP L exon 7 and SRSF3 exon 4 inclusion show poor overall survival.ConclusionsInclusion of hnRNP L alternative exon 7 is associated with good prognosis and inhibited by oncogene SRSF3 in HNSCC.
| S-EPMC6885243 | biostudies-literature
Project description:Ki67-mediated chromatin accessibility impedes B-cell antigen-receptor gene rearrangement
| PRJNA1035491 | ENA
Project description:ZO-1α+ and ZO-1α- proteins are expressed in hermetic and leaky tight junctions, respectively. Two cis-acting distant exonic elements partly activate the 240 nucleotide-long α exon producing the ZO-1α+ isoform. However, the elements within and around the α exon and their respective factors involved in its splicing are unknown. To study the dynamic interaction between SRSF3 and its bioinformatically predicted target sites around the 3'ss upstream of the α exon during its activation, we performed EMSA, crosslinking, and in vivo splicing assays by ZO-1 minigene expression and siRNA-mediated silencing in transfected cells. Using V1 RNase, we probed the possible formation of a hairpin RNA structure between the intronic and proximal exonic SRSF3 binding sites. The hairpin sufficed for complex formations in the EMSA. The interaction of SRSF3 with the intronic site promoted the cooperative binding of SRSF3 to the exonic site. Finally, SRSF3 restored α exon activation in SRSF3 knockdown transfectants. Altogether, our results show that SRSF3-hairpin RNA interaction is crucial in the early recognition of 3'ss for α exon activation. It remains to be explored whether SRSF3 recruits or stabilizes the binding of other factors or brings separate splice sites into proximity.
| S-EPMC9857539 | biostudies-literature
Project description:BCL-2 interacting cell death suppressor (BIS), also known as BAG3, is a multifunctional protein. Aberrant expression and mutation of BIS have been implicated in cancers and myopathy. However, there have only been a few studies on the splicing of BIS pre-mRNA. In the present study, through RT-PCR and sequencing in various cell lines and mouse tissues, we identified for the first time the presence of BIS mRNA isomers in which exon 3 or exons 2-3 are skipped. We also demonstrated that the depletion of SRSF3 promoted the skipping of exon 3 of BIS pre-mRNA in endogenous BIS and the GFP-BIS minigene. SRSF3 specifically interacts with the putative binding sites in exon 3, in which deletion promoted the skipping of exon 3 in the GFP-BIS minigene, which was comparable to the effect of SRSF knockdown. Even though acceleration of exon 3 skipping was not observed in response to various stimuli, SRSF3 depletion, accompanied by the production of a truncated BIS protein, inhibited the nuclear translocation of HSF1, which was restored by the wild-type BIS, not by exon 3-depleted BIS. Therefore, our results suggested that the maintenance of SRSF3 levels and subsequent preservation of the intact BIS protein is an important factor in modulating HSF1 localization upon cellular stress.
| S-EPMC7589869 | biostudies-literature