SYTL4 downregulates microtubule stability and confers paclitaxel resistance in triple-negative breast cancer

Autor: Xiao-En Xu, Ding Ma, Zhi-Ming Shao, Li-Ping Ge, Wang Jiang, Zong-Chao Gou, Xi-Yu Liu, Yun-Song Yang, Yi-Zhou Jiang
Rok vydání: 2020
Předmět:
0301 basic medicine
Small interfering RNA
Intravital Microscopy
Vesicular Transport Proteins
Medicine (miscellaneous)
Triple Negative Breast Neoplasms
Microtubules
Microtubule polymerization
Mice
0302 clinical medicine
Tubulin
Tumor Cells
Cultured
Breast
RNA-Seq
Pharmacology
Toxicology and Pharmaceutics (miscellaneous)
Mastectomy
Triple-negative breast cancer
microtubule polymerization
Chemistry
Effector
Middle Aged
Prognosis
Neoadjuvant Therapy
paclitaxel resistance
Gene Expression Regulation
Neoplastic
Organoids
Chemotherapy
Adjuvant
Gene Knockdown Techniques
030220 oncology & carcinogenesis
Female
Research Paper
Adult
Adolescent
Paclitaxel
SYTL4
Down-Regulation
Disease-Free Survival
Young Adult
03 medical and health sciences
Downregulation and upregulation
In vivo
Microtubule
Cell Line
Tumor
Animals
Humans
030104 developmental biology
Drug Resistance
Neoplasm
Cancer research
Rab
Neoplasm Recurrence
Local
Protein Multimerization
Zdroj: Theranostics
ISSN: 1838-7640
DOI: 10.7150/thno.45207
Popis: Background: Taxanes are frontline chemotherapeutic drugs for patients with triple-negative breast cancer (TNBC); however, chemoresistance reduces their effectiveness. We hypothesized that the molecular profiling of tumor samples before and after neoadjuvant chemotherapy (NAC) would help identify genes associated with drug resistance. Methods: We sequenced 10 samples by RNA-seq from 8 NAC patients with TNBC: 3 patients with a pathologic complete response (pCR) and the other 5 with non-pCR. Differentially expressed genes that predicted chemotherapy response were selected for in vitro functional screening via a small-scale siRNAs pool. The clinical and functional significance of the gene of interest in TNBC was further investigated in vitro and in vivo, and biochemical assays and imaging analysis were applied to study the mechanisms. Results: Synaptotagmin-like 4 (SYTL4), a Rab effector in vesicle transport, was identified as a leading functional candidate. High SYTL4 expression indicated a poor prognosis in multiple TNBC cohorts, specifically in taxane-treated TNBCs. SYTL4 was identified as a novel chemoresistant gene as validated in TNBC cells, a mouse model and patient-derived organoids. Mechanistically, downregulating SYTL4 stabilized the microtubule network and slowed down microtubule growth rate. Furthermore, SYTL4 colocalized with microtubules and interacted with microtubules through its middle region containing the linker and C2A domain. Finally, we found that SYTL4 was able to bind microtubules and inhibit the in vitro microtubule polymerization. Conclusion: SYTL4 is a novel chemoresistant gene in TNBC and its upregulation indicates poor prognosis in taxane-treated TNBC. Further, SYTL4 directly binds microtubules and decreases microtubule stability.
Databáze: OpenAIRE
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