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Merging Absolute and Relative Quantitative PCR Data to Quantify STAT3 Splice Variant Transcripts
Published on: October 9, 2016
PCBP1 inhibits the expression of oncogenic STAT3 isoform by targeting alternative splicing of STAT3 exon 23
Xiaole Wang1, Jihua Guo1,2, Xiaoxuan Che1
1The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, PR China.
Abstract:
STAT3 plays very important roles in the initiation and development of tumors. Despite of extensive studies in repressing its activation and function via multiple ways, so far, there are few effective therapeutic methods to inhibit STAT3 in the clinic. STAT3 has two isoforms generated by alternative splicing of exon 23. STAT3α is the longer isoform and encodes the full-length oncogenic STAT3α protein. STAT3β is shorter and encodes the truncated and tumor-suppressive STAT3β protein. It remains unknown how the alternative splicing of STAT3 exon 23 is regulated. Here, we discovered that there is an exonic splicing suppressor (ESS) in exon 23. Importantly, splicing factor PCBP1 binds to this ESS. Overexpression of PCBP1 significantly reduced the proportion of STAT3α /STAT3β isoforms and the expression of STAT3α protein. Moreover, increased PCBP1 inhibited the growth of oral squamous cell carcinoma and breast cancer cells, and the expression of STAT3 target genes. Our results demonstrated that PCBP1 is the key splicing factor that promotes the switch from oncogenic isoform STAT3α to tumor-suppressive isoform STAT3β. Our results pave the way for finding new anti-STAT3 methods for cancer treatment.
Insights
Researchers discovered that PCBP1 regulates STAT3 splicing, switching from the oncogenic STAT3α isoform to the tumor-suppressive STAT3β isoform. This finding offers new therapeutic strategies for cancer treatment.
Area of Science:
- Molecular Biology
- Cancer Research
- Gene Regulation
Background:
- Signal transducer and activator of transcription 3 (STAT3) is crucial in tumor initiation and progression.
- Existing therapies targeting STAT3 activation have limited clinical efficacy.
- STAT3 exists in two isoforms, STAT3α (oncogenic) and STAT3β (tumor-suppressive), generated by alternative splicing of exon 23.
Purpose of the Study:
- To elucidate the regulatory mechanism of STAT3 alternative splicing at exon 23.
- To identify key splicing factors involved in the STAT3 isoform switch.
Main Methods:
- Identification of an exonic splicing suppressor (ESS) in STAT3 exon 23.
- Investigation of the interaction between PCBP1 and the ESS.
- Analysis of PCBP1 overexpression effects on STAT3 isoform ratios and cancer cell growth.
Main Results:
- PCBP1 binds to the ESS in STAT3 exon 23.
- PCBP1 overexpression significantly decreases the STAT3α/STAT3β ratio and STAT3α protein levels.
- Increased PCBP1 inhibits oral squamous cell carcinoma and breast cancer cell proliferation and reduces STAT3 target gene expression.
Conclusions:
- PCBP1 acts as a critical splicing factor promoting the switch from oncogenic STAT3α to tumor-suppressive STAT3β.
- PCBP1's role in regulating STAT3 isoforms presents a novel therapeutic target for cancer treatment.
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