PLEKHA5 regulates tumor growth in metastatic melanoma

Abstract

Background PLEKHA5 has previously been identified as a novel molecule implicated in melanoma brain metastasis, a disease that continues to portend a poor prognosis. The aim of this study was to further investigate the functional role of PLEKHA5 in disseminated melanoma. Methods The impact of PLEKHA5 on proliferation and tumor growth was examined in vitro and in melanoma xenograft models, including brain‐tropic melanomas (melanomas tending to disseminate to the brain). In vitro loss‐ and gain‐of‐function studies were used to explore the underlying mechanisms of PLEKHA5‐mediated tumor growth and the crosstalk between PLEKHA5 and PI3K/AKT/mTOR or MAPK/ERK signaling. The clinical relevance of PLEKHA5 dysregulation was further investigated in a cohort of matched cranial and extracranial melanoma metastases. Results PLEKHA5 stable knockdown negatively regulated cell proliferation by inhibiting the G1‐to‐S cell cycle transition, which coincided with upregulation of the cell cycle regulator PDCD4. Conversely, ectopic PLEKHA5 expression exhibited the inverse effect. PLEKHA5 knockdown significantly inhibited tumor growth, whereas its overexpression upregulated the growth of tumors, which was induced by cranial and subcutaneous inoculation of cells in nude mice. PLEKHA5 modulation affected PDCD4 protein stability and was coupled with changes in PI3K/AKT/mTOR pathway signaling. High PDCD4 expression in cerebral specimens was associated with better overall survival. Conclusions This study further supports the role of PLEKHA5 as a regulator of melanoma growth at distant sites, including the brain. Furthermore, the results highlight the significance of PDCD4 dysregulation in disseminated melanoma and implicate PDCD4 as a possible causal link between PLEKHA5 and cell proliferation and growth.

Clinical Significance of PDCD4 in Melanoma by Subcellular Expression and in Tumor-Associated Immune Cells

“…We previously established Pleckstrin Homology Domain Containing A5 ( PLEKHA5 ), a gene involved in normal brain development, as a regulator of melanoma growth in brain metastasis [ 22 ]. Our data suggested that PLEKHA5-mediated growth could be attributed to its role in regulating the cell cycle inhibitor, programmed cell death 4 (PDCD4), via crosstalk with the ubiquitin-proteasome and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathways critical in PDCD4 complex regulation [ 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. Our study of paired cranial and extracranial human melanomas showed that high PDCD4 expression in cerebral specimens is significantly associated with improved survival, suggesting a role for PDCD4 loss in dysregulating melanoma brain metastasis [ 22 ].…”

“…In a small cohort of primary melanomas, low cellular PDCD4 mRNA levels correlated with increased tumor size, high Clark level, and lymph node metastases [ 30 ]. Our group reported prognostic significance of total PDCD4 protein levels (cytoplasmic and nuclear) by quantitative immunofluorescence (QIF) in a small cohort of melanoma metastases and shorter survival among patients with absent or low levels of PDCD4 in cerebral lesions [ 22 ].…”

“…In tumor cells, PDCD4 shuttles between the two compartments, and its nuclear localization and total protein expression are lost during disease progression [ 38 , 39 ]. We previously found predominantly cytoplasmic PDCD4 staining in cerebral compared to paired extracerebral metastases [ 22 ]. However, the sample size of our study ( n = 37) was not large enough to define the prognostic value of PDCD4 staining patterns in stratified analyses.…”

Biosynthetic circ-PLEKHA5 stabilized by SRSF7 promotes the vasculogenic mimicry of glioblastoma cells by encoding a novel protein 622aa

“…In addition, PLEKHA5 is also been found to abundantly expressed in the cytoplasm and cell membrane, and closely related to the process of cell migration and vascular formation [27] . In the cell model of brain metastasis of melanoma, knockdown of PLEKHA5 inhibits the proliferation of tumor cells, blocks cell cycle at G1-S progression, thereby inhibiting the tumorigenesis of tumor cells in vivo [28] . CircRNAs is a class of endogenous RNA with an atypical structure of covalently binding of 5'-and 3'-ends.…”

“…Due to the PH domain that PLEKHA5 contains, PLEKHA5 was supposedly to be associated with multiple phosphoinositide binding properties and PI3K-AKT pathway, thereby participating in intracellular functions [44] . It was reported that the expression of phosphorylated AKT (p-Akt) was decreased in PLEKHA5-depleted melanoma cells [28] . By scanning the amino acid sequence, PH domain was also found in circ-PLEKHA5-622aa.…”