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Updated: Jun 20, 2025
Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
RHBDF1 modulates cisplatin sensitivity of small cell lung cancer through YAP1/Smad2 signaling pathway
Lei Wang1, Lishuang Qi2, Xiaoyi Huang3,4
1Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, 150081, China.
Abstract:
Small cell lung cancer (SCLC) is a fatal tumor type that is prone to drug resistance. In our previous study, we showed that human rhomboid-5 homolog-1 (RHBDF1) was differentially expressed in 5 intrinsic cisplatin-resistant SCLC tissues compared with 5 intrinsic cisplatin-sensitive SCLC tissues by RNA sequencing, which intrigued us. We performed gain- and loss-of-function experiments to investigate RHBDF1 function, bioinformatics analysis, qRT-PCR, western blotting, and immunoprecipitation to elucidate the molecular mechanisms as well as detect RHBDF1 expression in SCLC by immunohistochemistry. We found that RHBDF1 knockdown promoted cell proliferation and cisplatin chemoresistance and inhibited apoptosis in vitro and in vivo. These effects could be reversed by overexpressing RHBDF1 in vitro. Mechanistically, RHBDF1 interacted with YAP1, which increased the phosphorylation of Smad2 and transported Smad2 to the nucleus. Among clinical specimens, the RHBDF1 was a low expression in SCLC and was associated with clinicopathological features and prognosis. We are the first to reveal that RHBDF1 inhibited cell proliferation and promoted cisplatin sensitivity in SCLC and elucidate a novel mechanism through RHBDF1/YAP1/Smad2 signaling pathway which played a crucial role in cisplatin chemosensitivity. Targeting this pathway can be a promising therapeutic strategy for chemotherapy resistance in SCLC.
Insights
Human rhomboid-5 homolog-1 (RHBDF1) suppresses tumor growth and enhances cisplatin sensitivity in small cell lung cancer (SCLC). Low RHBDF1 expression correlates with poor prognosis, suggesting RHBDF1 as a therapeutic target for SCLC chemoresistance.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Small cell lung cancer (SCLC) is a highly aggressive malignancy characterized by rapid progression and frequent development of drug resistance.
- Cisplatin is a cornerstone chemotherapy agent for SCLC, but intrinsic and acquired resistance significantly limit its clinical efficacy.
- Human rhomboid-5 homolog-1 (RHBDF1) was identified as a differentially expressed gene in cisplatin-resistant SCLC tissues, prompting investigation into its role.
Purpose of the Study:
- To investigate the functional role of RHBDF1 in SCLC proliferation, apoptosis, and cisplatin chemosensitivity.
- To elucidate the molecular mechanisms underlying RHBDF1's function in SCLC.
- To evaluate the clinical significance of RHBDF1 expression in SCLC patient samples.
Main Methods:
- Gain- and loss-of-function experiments (RHBDF1 knockdown and overexpression) were performed in SCLC cell lines.
- Molecular mechanisms were investigated using bioinformatics analysis, quantitative real-time PCR (qRT-PCR), western blotting, and immunoprecipitation.
- RHBDF1 expression in clinical SCLC specimens was assessed by immunohistochemistry.
Main Results:
- RHBDF1 knockdown promoted SCLC cell proliferation, enhanced cisplatin chemoresistance, and inhibited apoptosis both in vitro and in vivo.
- Overexpression of RHBDF1 reversed these effects, restoring cisplatin sensitivity and promoting apoptosis.
- Mechanistically, RHBDF1 was found to interact with YAP1, leading to increased Smad2 phosphorylation and nuclear translocation, thereby inhibiting proliferation and enhancing chemosensitivity.
- Low RHBDF1 expression was observed in clinical SCLC specimens and correlated with adverse clinicopathological features and poor prognosis.
Conclusions:
- RHBDF1 functions as a tumor suppressor in SCLC, inhibiting proliferation and promoting cisplatin sensitivity.
- The novel RHBDF1/YAP1/Smad2 signaling pathway plays a critical role in regulating cisplatin chemosensitivity in SCLC.
- Targeting the RHBDF1/YAP1/Smad2 pathway represents a promising therapeutic strategy to overcome chemotherapy resistance in SCLC.
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