Serum Actinin-4 Levels as a Potential Diagnostic and Prognostic Marker in Cervical Cancer

Ma, Xigui; Xue, Hao; Zhong, Jixiang; Feng, Bo; Zuo, Yunxia

doi:10.1155/2020/5327378

“…Interestingly, ACTN4 has been shown to play a key role in the progression of cervical cancer. High levels of ACTN4 are observed in cervical cancer and associated with a poor prognosis 45 . Upregulation of ACTN4 promotes the proliferation and invasion of cervical cancer 19,46 .…”

Section: Discussionmentioning

confidence: 99%

TRIP13 exerts a cancer‐promoting role in cervical cancer by enhancing Wnt/β‐catenin signaling via ACTN4

Liu

¹

,

Shen

²

,

Zhang

³

2021

Environmental Toxicology

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Increasing evidence has indicated that thyroid hormone receptor interacting protein 13 (TRIP13) exerts a cancer‐promoting role in a broad spectrum of cancers. However, the detailed relevance and function of TRIP13 in cervical cancer remain undefined. The goal of this work was to evaluate the functional significance and mechanism of TRIP13 in cervical cancer. Our data demonstrated that TRIP13 expression was markedly increased in cervical cancer tissue, and high expression of TRIP13 predicted a low survival rate in cervical cancer patients. Knockdown of TRIP13 caused a significant reduction in the proliferation and invasion of cervical cancer cells. By contrast, over‐expression of TRIP13 accelerated the proliferation and invasion of cervical cancer cells. Further data revealed that TRIP13 enhanced the activation of Wnt/β‐catenin signaling associated with modulation of α‐Actinin‐4 (ACTN4). Knockdown of ACTN4 markedly reversed TRIP13‐mediated activation of Wnt/β‐catenin signaling. In addition, inhibition of Wnt/β‐catenin signaling reversed TRIP13‐induced cancer‐promoting effects in cervical cancer cells. Knockdown of TRIP13 markedly retarded the tumor formation and growth of cervical cells in vivo in nude mice. Taken together, the data of this work indicate that TRIP13 accelerates the proliferation and invasion of cervical cancer by enhancing Wnt/β‐catenin signaling via regulation of ACTN4. These findings underscore a relevance of the TRIP13/ACTN4/Wnt/β‐catenin signaling axis in the progression of cervical cancer and suggest TRIP13 as a potential target for treatment of cervical cancer.

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“…For instance, 14-3-3ε has been found to function as a soluble mediator critical in the communication between subchondral bone and cartilage in osteoarthritis [65]. Similarly, elevated levels of serum α-actinin 4 are associated with lymph node metastasis and a poorer prognosis in cervical cancer [66].…”

Section: Introductionmentioning

confidence: 99%

AGR2-mediated unconventional secretion of 14-3-3ε and α-actinin-4, responsive to ER stress and autophagy, drives chemotaxis in canine mammary tumor cells

Yuan,

Wu,

Wang

et al. 2024

Cell Mol Biol Lett

1

0

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Background Canine mammary tumors (CMTs) in intact female dogs provide a natural model for investigating metastatic human cancers. Our prior research identified elevated expression of Anterior Gradient 2 (AGR2), a protein disulfide isomerase (PDI) primarily found in the endoplasmic reticulum (ER), in CMT tissues, highly associated with CMT progression. We further demonstrated that increased AGR2 expression actively influences the extracellular microenvironment, promoting chemotaxis in CMT cells. Unraveling the underlying mechanisms is crucial for assessing the potential of therapeutically targeting AGR2 as a strategy to inhibit a pro-metastatic microenvironment and impede tumor metastasis. Methods To identify the AGR2-modulated secretome, we employed proteomics analysis of the conditioned media (CM) from two CMT cell lines ectopically expressing AGR2, compared with corresponding vector-expressing controls. AGR2-regulated release of 14-3-3ε (gene: YWHAE) and α-actinin 4 (gene: ACTN4) was validated through ectopic expression, knockdown, and knockout of the AGR2 gene in CMT cells. Extracellular vesicles derived from CMT cells were isolated using either differential ultracentrifugation or size exclusion chromatography. The roles of 14-3-3ε and α-actinin 4 in the chemotaxis driven by the AGR2-modulated CM were investigated through gene knockdown, antibody-mediated interference, and recombinant protein supplement. Furthermore, the clinical relevance of the release of 14-3-3ε and α-actinin 4 was assessed using CMT tissue-immersed saline and sera from CMT-afflicted dogs. Results Proteomics analysis of the AGR2-modulated secretome revealed increased abundance in 14-3-3ε and α-actinin 4. Ectopic expression of AGR2 significantly increased the release of 14-3-3ε and α-actinin 4 in the CM. Conversely, knockdown or knockout of AGR2 expression remarkably reduced their release. Silencing 14-3-3ε or α-actinin 4 expression diminished the chemotaxis driven by AGR2-modulated CM. Furthermore, AGR2 controls the release of 14-3-3ε and α-actinin 4 primarily via non-vesicular routes, responding to the endoplasmic reticulum (ER) stress and autophagy activation. Knockout of AGR2 resulted in increased α-actinin 4 accumulation and impaired 14-3-3ε translocation in autophagosomes. Depletion of extracellular 14-3-3ε or α-actinin 4 reduced the chemotaxis driven by AGR2-modulated CM, whereas supplement with recombinant 14-3-3ε in the CM enhanced the CM-driven chemotaxis. Notably, elevated levels of 14-3-3ε or α-actinin 4 were observed in CMT tissue-immersed saline compared with paired non-tumor samples and in the sera of CMT dogs compared with healthy dogs. Conclusion This study elucidates AGR2’s pivotal role in orchestrating unconventional secretion of 14-3-3ε and α-actinin 4 from CMT cells, thereby contributing to paracrine-mediated chemotaxis. The insight into the intricate interplay between AGR2-involved ER stress, autophagy, and unconventional secretion provides a foundation for refining strategies aimed at impeding metastasis in both canine mammary tumors and potentially human cancers.

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“…Serum or cancer tissue biomarkers for the prediction of prognosis of cervical cancer have been reported [ 4 , 5 ]. The 5-year survival rate for overall cervical cancer is 66%, which is affected by race, ethnicity, age, and stage [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Body Weight Is a Valid Predictor of the Long-Term Prognosis of Cervical Cancer

Lu

¹

,

Ji

²

,

Jiang

³

et al. 2022

Computational and Mathematical Methods in Medicine

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Objective. To identify and validate effective clinical predictors for the long-term prognosis of patients with cervical cancer. Methods. Cervical cancer patients were retrieved from the TCGA database, and patients’ clinical data were collected and analyzed for the predictive value of long-term prognosis. In the other branch of the study, patients with cervical cancer and admitted to our hospital between January 1, 2016, and December 31, 2016, were retrieved and followed up for prognosis analysis. Results. In the database patient cohort of our study, 607 cases with cervical cancer were analyzed. Aneuploidy score ( p = 0.012 ), Buffa hypoxia score ( p = 0.013 ), histologic grade ( p = 0.01 ), fraction genome altered >0.4 ( p < 0.001 ), weight > 60 kg ( p < 0.001 ), height > 160 cm ( p = 0.047 ), BMI <18.5 ( p = 0.023 ), Winter hypoxia score ( p = 0.002 ), and adjuvant postoperative radiotherapy were good predictors for disease-free survival (DFS), while aneuploidy score ( p = 0.001 ), MSI sensor score > 0.5 ( p = 0.035 ), person neoplasm status ( p < 0.001 ), race ( p = 0.006 ), Ragnum hypoxia score ( p = 0.012 ), weight ( p < 0.001 ), height ( p < 0.001 ), and BMI < 18.5 ( p = 0.04 ) were good predictors for overall survival (OS). In the admitted patient cohort, age over 60 years old at the time of diagnosis was the only clinical factor influencing the long-term DFS ( p = 0.004 ). TNM stage above III ( p = 0.004 ), body weight > 70 kg ( p < 0.001 ), and complicated with other cancer ( p < 0.001 ) were clinical factor influencing the long-term OS. Conclusions. Clinical factors, especially common to both cohorts, could be used to show the long-term prognosis of cervical cancer.

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Serum Actinin-4 Levels as a Potential Diagnostic and Prognostic Marker in Cervical Cancer

Cited by 8 publications

References 25 publications

TRIP13 exerts a cancer‐promoting role in cervical cancer by enhancing Wnt/β‐catenin signaling via ACTN4

TRIP13 exerts a cancer‐promoting role in cervical cancer by enhancing Wnt/β‐catenin signaling via ACTN4

AGR2-mediated unconventional secretion of 14-3-3ε and α-actinin-4, responsive to ER stress and autophagy, drives chemotaxis in canine mammary tumor cells

Body Weight Is a Valid Predictor of the Long-Term Prognosis of Cervical Cancer

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