SKA3 promotes lung adenocarcinoma metastasis through the EGFR–PI3K–Akt axis

Hu, Dandan; Chen, Hailing; Lou, Liming; Zhang, Hong; Yang, Guoliang

doi:10.1042/bsr20194335

Cited by 34 publications

(44 citation statements)

References 32 publications

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“…However, according to our results, SKA3 proteins in uenced the progression of HCC and PAAD tumors. Therefore, we speculated that SKA3 could have different biological functions in both tumors, an observation that is contrary to previous studies [22,27].…”

Section: Discussioncontrasting

confidence: 87%

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Expression of Spindle and Kinetochore-related Complex Subunit 3 is Associate With the Progression and Prognosis of Hepatocellular Carcinoma and Pancreatic Adenocarcinoma

Su¹,

Huang²,

Xie³

et al. 2020

Preprint

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Abstract Background Several studies have shown that Spindle and Kinetochore-related Complex Subunit 3 (SKA3) is closely related to the diagnosis and prognosis of various cancers. SKA3 plays a vital role in mitosis, but the mechanism underlying its action in tumors has not been fully elucidated. Methods Two separate microarrays of pancreatic adenocarcinoma (PAAD) and hepatocellular carcinoma (HCC) samples were downloaded from the Gene Expression Omnibus (GEO) and analyzed using R software. Tissues from 203 HCC and 321 PAAD patients were used for tissue microarray (TMA) construction and immunohistochemical staining for scoring. Kaplan-Meier estimators were used to determine their clinical relevance. Finally, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomics (KEGG) were used for analyzed rich pathways of SKA3 to understand gene function further. Results Contrary to the results obtained from the GEO database, HCC and PAAD tumor tissues exhibited significantly lower expression of SKA3 compared to the adjacent tissues (P < 0.001). The size of HCC tumor and Edmondson grade were statistically correlated with SKA3 expression (P < 0.05). No correlation was observed between the levels of SKA3 expression and vascular invasion, metastasis, or lymphatic infiltration in HCC patients. Moreover, factors related to decreases of SKA3 in PAAD could similarly not be found. Kaplan-Meier survival curves indicated that SKA3 upregulation in HCC was significantly associated with better prognosis (P = 0.016). In contrast, low levels of SKA3 were related to poor prognosis of PAAD patients (P = 0.026). Enrichment analysis of GO and KEGG pathways showed that SKA3 gene was closely related to cell cycle pathways. Conclusions The results of the present study indicate that SKA3 expression can serve as a diagnostic and prognostic biomarker for HCC and PAAD. However, there is a need to conduct further studies to verify these findings, especially the prognostic role of SKA3 in PAAD.

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Section: Discussioncontrasting

confidence: 87%

“…SKA3 is one of the important cyclins. Although some studies have suggested that SKA3 could in uence the progression of certain cancers [22,23], the mechanism underlying its role is still largely unclear and controversial [24][25][26]. Herein, we explored the relationship between SKA3 and the diagnosis and prognosis of HCC and PAAD.…”

Section: Discussionmentioning

confidence: 99%

Expression of Spindle and Kinetochore-related Complex Subunit 3 is Associate With the Progression and Prognosis of Hepatocellular Carcinoma and Pancreatic Adenocarcinoma

Su¹,

Huang²,

Xie³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…As an important component of the spindle and kinetochore-related complexes 29 , SKA3 is essential for regulating mitosis with NDC80 complex and thus controlling cell proliferation and apoptosis 26 , 30 . Aberrant expression of SKA3 is closely associated with tumorigenesis and development 14 , 30 . For instance, SKA3 binds EGFR and consequently activates PI3K–AKT, thus promoting lung adenocarcinoma metastasis 14 .…”

Section: Discussionmentioning

confidence: 99%

“…Aberrant expression of SKA3 is closely associated with tumorigenesis and development 14 , 30 . For instance, SKA3 binds EGFR and consequently activates PI3K–AKT, thus promoting lung adenocarcinoma metastasis 14 . However, although EGFR mutation is rare in LSCC, SKA3-mediated AKT activation mainly depends on the serine/threonine-protein kinase PLK1 as silencing of PLK1 significantly attenuated the increase in p-AKT caused by SKA3 overexpression (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Knockdown of SKA3 expression activates the spindle assembly checkpoint with loss of sister chromatid cohesion, leading to mitotic arrest during metaphase 12 , 13 . SKA3 is implicated in the development and progress of lung adenocarcinoma, prostate cancer, cervical cancer, and breast cancer 14 – 17 . Here, we show that SKA3 is also highly expressed in LSCC, and higher levels of SKA3 are closely associated with poorer clinicopathological characteristics.…”

Section: Introductionmentioning

confidence: 99%

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Targeting SKA3 suppresses the proliferation and chemoresistance of laryngeal squamous cell carcinoma via impairing PLK1–AKT axis-mediated glycolysis

et al. 2020

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Spindle and kinetochore-associated complex subunit 3 (SKA3) is a well-known regulator of chromosome separation and cell division, which plays an important role in cell proliferation. However, the mechanism of SKA3 regulating tumor proliferation via reprogramming metabolism is unknown. Here, SKA3 is identified as an oncogene in laryngeal squamous cell carcinoma (LSCC), and high levels of SKA3 are closely associated with malignant progression and poor prognosis. In vitro and in vivo experiments demonstrate that SKA3 promotes LSCC cell proliferation and chemoresistance through a novel role of reprogramming glycolytic metabolism. Further studies reveal the downstream mechanisms of SKA3, which can bind and stabilize polo-like kinase 1 (PLK1) protein via suppressing ubiquitin-mediated degradation. The accumulation of PLK1 activates AKT and thus upregulates glycolytic enzymes HK2, PFKFB3, and PDK1, resulting in enhancement of glycolysis. Furthermore, our data reveal that phosphorylation at Thr360 of SKA3 is critical for its binding to PLK1 and the increase in glycolysis. Collectively, the novel oncogenic signal axis “SKA3-PLK1-AKT” plays a critical role in the glycolysis of LSCC. SKA3 may serve as a prognostic biomarker and therapeutic target, providing a potential strategy for proliferation inhibition and chemosensitization in tumors, especially for LSCC patients with PLK1 inhibitor resistance.

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EGFR‐rich extracellular vesicles derived from highly metastatic nasopharyngeal carcinoma cells accelerate tumour metastasis through PI3K/AKT pathway‐suppressed ROS

Zhao

Sun

et al. 2020

J of Extracellular Vesicle

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Nasopharyngeal carcinoma (NPC) is the most common cancer with high metastatic potential that occurs in the epithelial cells of the nasopharynx. Distant metastases are the primary cause for treatment failure and mortality of NPC patients. However, the underlying mechanism responsible for the initiation of tumour cell dissemination and tumour metastasis in NPC is not well understood. Here, we demonstrated that epidermal growth factor receptor (EGFR) was highly expressed in tumour tissues of NPC patients with distant metastases and was associated with a decrease in reactive oxygen species (ROS). We also revealed that extracellular vesicles (EVs) transfer occurred from highly to poorly metastatic NPC cells, mediating cell–cell communication and enhancing the metastatic potential of poorly metastatic NPC cells. Further experiments indicated that EVs derived from highly metastatic NPC cells induced the up‐regulation of EGFR and down‐regulation of ROS in low metastatic NPC cells. Mechanistically, EGFR‐rich EVs‐mediated EGFR overexpression down‐regulated intracellular ROS levels through the PI3K/AKT pathway, thus promoting the metastatic potential of poorly metastatic NPC cells. Strikingly, treatment with EVs secreted from highly metastatic NPC cells was significantly associated with rapid NPC progression and shorter survival in xenografted mice. These findings not only improve our understanding of EVs‐mediated NPC metastatic mechanism but also have important implications for the detection and treatment of NPC patients accompanied by aberrant EGFR‐rich EVs transmission.

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SKA3 promotes lung adenocarcinoma metastasis through the EGFR–PI3K–Akt axis

Cited by 34 publications

References 32 publications

Expression of Spindle and Kinetochore-related Complex Subunit 3 is Associate With the Progression and Prognosis of Hepatocellular Carcinoma and Pancreatic Adenocarcinoma

Expression of Spindle and Kinetochore-related Complex Subunit 3 is Associate With the Progression and Prognosis of Hepatocellular Carcinoma and Pancreatic Adenocarcinoma

Targeting SKA3 suppresses the proliferation and chemoresistance of laryngeal squamous cell carcinoma via impairing PLK1–AKT axis-mediated glycolysis

EGFR‐rich extracellular vesicles derived from highly metastatic nasopharyngeal carcinoma cells accelerate tumour metastasis through PI3K/AKT pathway‐suppressed ROS

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