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Small Protein Hidden in lncRNA LOC90024 Promotes "Cancerous" RNA Splicing and Tumorigenesis
Abstract:
Conventional therapies for late-stage colorectal cancer (CRC) have limited effects because of chemoresistance, recurrence, and metastasis. The "hidden" proteins/peptides encoded by long noncoding RNAs (lncRNAs) may be a novel resource bank for therapeutic options for patients with cancer. Here, lncRNA LOC90024 is discovered to encode a small 130-amino acid protein that interacts with several splicing regulators, such as serine- and arginine-rich splicing factor 3 (SRSF3), to regulate mRNA splicing, and the protein thus is named "Splicing Regulatory Small Protein" (SRSP). SRSP, but not LOC90024 lncRNA itself, promotes CRC tumorigenesis and progression, while silencing of SRSP suppresses CRC tumorigenesis. Mechanistically, SRSP increases the binding of SRSF3 to exon 3 of transcription factor Sp4, resulting in the inclusion of Sp4 exon 3 to induce the formation of the "cancerous" long Sp4 isoform (L-Sp4 protein) and inhibit the formation of the "noncancerous" short Sp4 isoform (S-Sp4 peptide), which lacks the transactivation domain. The upregulated SRSP level is positively associated with malignant phenotypes and poor prognosis in patients with CRC. Collectively, the findings uncover that a lncRNA-encoded small protein SRSP induces "cancerous" Sp4 splicing variant formation and may be a potential prognostic biomarker and therapeutic target for patients with CRC.
Insights
A newly discovered small protein, Splicing Regulatory Small Protein (SRSP), encoded by the lncRNA LOC90024, drives colorectal cancer progression. Silencing SRSP inhibits tumor growth, suggesting SRSP as a potential therapeutic target for colorectal cancer.
Area of Science:
- Molecular Biology
- Oncology
- Genetics
Background:
- Late-stage colorectal cancer (CRC) presents therapeutic challenges due to chemoresistance, recurrence, and metastasis.
- Long noncoding RNAs (lncRNAs) are increasingly recognized for their potential to encode therapeutic targets.
- Identifying novel molecular mechanisms is crucial for advancing CRC treatment.
Purpose of the Study:
- To investigate the role of the lncRNA LOC90024 and its encoded protein in colorectal cancer.
- To elucidate the mechanism by which this protein influences CRC tumorigenesis and progression.
- To evaluate the potential of this protein as a prognostic biomarker and therapeutic target for CRC.
Main Methods:
- Identification and characterization of a novel protein encoded by the lncRNA LOC90024.
- Investigation of the protein's interaction with splicing regulators, specifically SRSF3.
- Analysis of the protein's effect on mRNA splicing, focusing on the Sp4 transcription factor.
- Assessment of the protein's role in CRC cell lines and correlation with patient prognosis.
Main Results:
- The lncRNA LOC90024 encodes a 130-amino acid protein named Splicing Regulatory Small Protein (SRSP).
- SRSP promotes CRC tumorigenesis and progression by enhancing SRSF3 binding to Sp4 exon 3, favoring the "cancerous" L-Sp4 isoform.
- Silencing SRSP suppressed CRC tumorigenesis, and elevated SRSP levels correlated with malignant phenotypes and poor prognosis in CRC patients.
Conclusions:
- The lncRNA-encoded protein SRSP is a key driver of colorectal cancer progression through aberrant Sp4 splicing.
- SRSP represents a promising novel prognostic biomarker and therapeutic target for colorectal cancer patients.
- Targeting SRSP may offer a new strategy to overcome limitations in current CRC therapies.
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