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A functional role for KLF6-SV1 in lung adenocarcinoma prognosis and chemotherapy response.

ABSTRACT: Kruppel-like factor 6 (KLF6) is a tumor suppressor gene that is functionally inactivated in human cancer by loss of heterozygosity, somatic mutation, decreased expression, and increased alternative splicing into an oncogenic splice variant, KLF6-SV1. Here we show that increased expression of KLF6-SV1 is associated with decreased survival in patients with lung adenocarcinoma. In addition, KLF6-SV1 is a novel antiapoptotic protein in lung cancer cell lines, and targeted reduction of KLF6-SV1 using siRNA induces apoptosis both alone and in combination with the chemotherapeutic drug cisplatin. Together, these findings highlight a critical role for KLF6-SV1 in lung cancer, and show a potential novel therapeutic strategy for the treatment of lung cancer.

SUBMITTER: DiFeo A

PROVIDER: S-EPMC2826216 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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A functional role for KLF6-SV1 in lung adenocarcinoma prognosis and chemotherapy response.

DiFeo Analisa A Feld Lauren L Rodriguez Estefania E Wang Christine C Beer David G DG Martignetti John A JA Narla Goutham G

Cancer research 20080204 4

Kruppel-like factor 6 (KLF6) is a tumor suppressor gene that is functionally inactivated in human cancer by loss of heterozygosity, somatic mutation, decreased expression, and increased alternative splicing into an oncogenic splice variant, KLF6-SV1. Here we show that increased expression of KLF6-SV1 is associated with decreased survival in patients with lung adenocarcinoma. In addition, KLF6-SV1 is a novel antiapoptotic protein in lung cancer cell lines, and targeted reduction of KLF6-SV1 using ...[more]

PMID: 18250346

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Targeted reduction of KLF6-SV1 restores chemotherapy sensitivity in resistant lung adenocarcinoma.

Project description:Kruppel-like factor 6 splice variant 1 (KLF6-SV1) is an oncogenic splice variant of the KLF6 tumor suppressor gene that is specifically overexpressed in a number of human cancers. Previously, we have demonstrated that increased expression of KLF6-SV1 is associated with decreased survival in lung adenocarcinoma patient samples and that targeted reduction of KLF6-SV1 using siRNA induced apoptosis both alone and in combination with the chemotherapeutic drug cisplatin. Here, we demonstrate that chemoresistant lung cancer cells express increased levels of KLF6-SV1. Furthermore, targeted reduction of KLF6-SV1 using RNA interference restores chemotherapy sensitivity to lung cancer cells both in culture and in vivo through induction of apoptosis. Conversely, overexpression of KLF6-SV1 resulted in a marked reduction in chemotherapy sensitivity in a tumor xenograft model. Combined, these findings highlight a functional role for the KLF6-SV1 splice variant in the regulation of chemotherapy response in lung cancer and could provide novel insight into lung cancer therapy.

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KLF6-SV1 is a new prognostic biomarker in postoperative patients with non-small cell lung cancer.

Project description:Objectives:Non-small cell lung cancer (NSCLC) is aggressive and associated with a poor prognosis. Recent studies have revealed that several genes are involved in the origin and progression of NSCLC. Kruppel-like factor 6 (KLF6) inactivation has been shown in some malignant tumors. KLF6-SV1, as one of the alternatively spliced KLF6 isoforms, has been found to be correlated with metastatic potential and poor survival in some cancers. The purpose of this study was to investigate the clinical and prognostic significance of KLF6-SV1 expression in NSCLC patients after curative resection. Patients and methods:A total of 79 patients were enrolled in this study. Enumeration data were analyzed using the chi-squared test or Fisher's exact probability test. Measurement data were represented as average±SD and t-test (homoscedasticity) or t'-test (homoscedasticity uneven). Univariate analysis was performed by modeling Kaplan-Meier survival curves. The log-rank test was used to calculate the survival rate. Multivariate analysis was carried out by the use of the Cox proportional hazard model. Results:KLF6-SV1 expression was correlated with pN (P<0.05) and pTNM stage (P<0.05). The expression of KLF6-SV1 in the adenocarcinoma group was significantly higher than that in the squamous cell carcinoma group (P<0.05). The 5-year survival rate for 79 NSCLC patients was 40.5%, and it was significantly associated with differentiation (P<0.05), pN (P<0.01), pTNM stage (P<0.01) and high expression of KLF6-SV1 (P<0.01). Cox multivariate regression demonstrated that differentiation, pN and KLF6-SV1 expression were independent factors for the 5-year survival rate. Conclusion:KLF6-SV1 expression in adenocarcinoma was significantly higher than that in the squamous cell carcinoma, and high expression of KLF6-SV1 was significantly associated with pN and pTNM stage and poor survival in NSCLC patients.

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Identification of miRNAs that specifically target tumor suppressive KLF6-FL rather than oncogenic KLF6-SV1 isoform.

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KLF6-SV1 drives breast cancer metastasis and is associated with poor survival.

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| S-EPMC4661785 | biostudies-literature

KLF6-SV1 overexpression accelerates human and mouse prostate cancer progression and metastasis.

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| S-EPMC2441856 | biostudies-literature

MiRNAs in Lung Adenocarcinoma: Role, Diagnosis, Prognosis, and Therapy

Project description: Not available

| S-EPMC10487838 | biostudies-literature

Kruppel like factor 6 splice variant 1 (KLF6-SV1) overexpression recruits macrophages to participate in lung cancer metastasis by up-regulating TWIST1.

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| S-EPMC6605981 | biostudies-literature

The prognosis, chemotherapy and immunotherapy efficacy of the SUMOylation pathway signature and the role of UBA2 in lung adenocarcinoma.

Project description:Lung adenocarcinoma (LUAD) is one of the most common malignant tumors worldwide. Small Ubiquitin-like Modifier (SUMO)-ylation plays a crucial role in tumorigenesis. However, the SUMOylation pathway landscape and its clinical implications in LUAD remain unclear. Here, we analyzed genes involved in the SUMOylation pathway in LUAD and constructed a SUMOylation pathway signature (SUMOPS) using the LASSO-Cox regression model, validated in independent cohorts. Our analysis revealed significant dysregulation of SUMOylation-related genes in LUAD, comprising of favorable or unfavorable prognostic factors. The SUMOPS model was associated with established molecular and histological subtypes of LUAD, highlighting its clinical relevance. The SUMOPS stratified LUAD patients into SUMOPS-high and SUMOPS-low subtypes with distinct survival outcomes and adjuvant chemotherapy responses. The SUMOPS-low subtype showed favorable responses to adjuvant chemotherapy. The correlations between SUMOPS scores and immune cell infiltration suggested that patients with the SUMOPS-high subtype exhibited favorable immune profiles for immune checkpoint inhibitor (ICI) treatment. Additionally, we identified UBA2 as a key SUMOylation-related gene with an increased expression and a poor prognosis in LUAD. Cell function experiment confirmed the role of UBA2 in promoting LUAD cell proliferation, invasion, and migration. These findings provide valuable insights into the SUMOylation pathway and its prognostic implications in LUAD, paving the way for personalized treatment strategies and the development of novel therapeutic targets.

| S-EPMC10968705 | biostudies-literature

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| S-EPMC10050597 | biostudies-literature

Investigating the functional role of SETD6 in lung adenocarcinoma.

Project description:BackgroundSET domain containing 6 (SETD6) has been shown to be upregulated in multiple human cancers and can promote malignant cell survival. However, expression and function of SETD6 in lung adenocarcinoma (LUAD) remains unaddressed. This study aimed to demonstrate the expression pattern, biological roles and potential mechanisms by which SETD6 dysregulation is associated with LUAD.MethodsThe expression level of SETD6 was evaluated in LUAD clinical specimens and its correlation with clinical parameters were analyzed. In vitro, gain-of-function and loss-of-function experiments were performed to evaluate the effects of SETD6 on cell proliferation, apoptosis, migration, and colony formation of LUAD cell line A549. Western-blot was performed to investigate the involvement of nuclear factor-κB (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways as downstream signaling of SETD6 in LUAD cells.ResultsCompared with non-tumorous tissues, SETD6 was overexpressed in tumor tissues, and its overexpression significantly correlates with higher rates of regional lymph node metastasis and poor prognosis in patients with LUAD. In A549 cell line, SETD6 overexpression could promote cell proliferation, migration, colony formation and inhibit cell apoptosis, whereas SETD6 knockdown caused the opposite effects. Furthermore, we demonstrated that the mechanisms underlying the effect of SETD6 on LUAD biological behaviors may be through its interaction with NF-κB and Nrf2 signaling pathways.ConclusionsSETD6, which is highly expressed in LUAD tumor tissues, plays an important role in promoting the malignant behaviors of LUAD via likely the NF-κB and Nrf2 signaling pathways.

| S-EPMC9817333 | biostudies-literature

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