StemCell Therapy

Introduction

Profilin 1 (PFN1) is a ubiquitous small-molecule protein that exists in all eukaryotes.1 PFN1 was first identified as a G-actin sequestering molecule,2 and subsequently, its true functions in actin polymerization and F-actin dynamics were revealed.3 In the following decades, the structure of PFN1 was recognized to have 3 domains: an actin-binding domain,4 a poly-L-proline (PLP)-binding domain,5 and a phosphoinositide-binding domain.6

PFN1 plays a vital role in many cell functions, including membrane trafficking, endocytosis, cell cycle, motility, proliferation, cell survival, transcription, stemness, and autophagy (Figure 1). Abnormal expression or deletion of PFN1 can affect the normal physiological activity of cells and lead to disease development. PFN1 has been deeply studied in a variety of diseases, some genetic (eg, amyotrophic lateral sclerosis)7 and some chronic (eg, hypertension).8

In the past 10 years, PFN1s role in cancer has received increasing attention. In this review, we summarize the studies of PFN1 in cancer that have been completed in recent years, discuss the roles of PFN1 in cancer, and discuss the implications for tumor diagnosis and therapy in the future.

Early diagnosis of cancers is still a major challenge worldwide, and early detection can notably reduce their associated morbidity and mortality.9 PFN1, a critical actin-binding protein, is found to be dysregulated in many cancers, which makes it possible to use it as a biomarker for diagnosis and prognosis. PFN1 mainly plays a role in the cytoplasm, but it can also be found in the nucleus and can even be secreted into the extracellular space. The rich knowledge in the proteomics field makes the detection of proteins for new diagnostic markers and targets for therapy possible.10

In some tumor types (such as renal cell carcinoma [RCC], gastric cancer, and others), high expression of PFN1 indicates later stage and worse prognosis. Via differential proteomics, PFN1 has been identified in metastatic and primary RCC, and further analysis indicated that high PFN1 expression was associated with poor outcome and that PFN1 could be used as a potential prognostic marker in RCC.11 In clear-cell RCC (ccRCC), the expression of PFN1 was decreased in early-stage tumors compared with normal tissues. However, its expression in stage IV ccRCC was significantly increased. PFN1 was selected as a candidate marker of late-stage ccRCC.12 Results of a recent study determined that the vast majority of ccRCC tumors tend to be selectively PFN1-positive in stromal cells only; dramatic transcriptional upregulation of PFN1 was found in tumor-associated vascular endothelial cells in clinical specimens of ccRCC.13 Tissue microarray results also showed that PFN1 was increased in metastatic ccRCC compared with primary tumors. Univariate analysis suggested that higher PFN1 expression was associated with shorter disease-free survival (HR, 7.36; P = .047) and lower overall survival.14

In gastric cancer, Tanaka et al found that PFN1 was highly expressed in fetal rat stomach. Additionally, PFN1 was overexpressed in some human and rat gastric cancers.15 The results of later studies indicated that PFN1 expression was higher in gastric cancer tissues than in adjacent normal tissues. High PFN1 expression was correlated with tumor infiltration, lymph node metastasis, and tumor-node-metastases (TNM) stage. Functional assays confirmed that silencing PFN1 could inhibit the invasion and migration of gastric cancer cell lines.16

In addition, PFN1 expression was higher in nonsmall cell lung cancer (NSCLC). Lower expression of PFN1 was associated with better prognosis and a higher survival rate in NSCLC.17 Proteomic analysis revealed that PFN1 was differentially expressed in laryngeal carcinoma tissues compared with adjacent normal tissues. Further study results revealed that PFN1 was increased in laryngeal carcinoma tissues compared with adjacent normal tissues, indicating that PFN1 was a novel potential biomarker for the diagnosis of laryngeal carcinoma.18

However, in some other tumors (such as colorectal cancer [CRC], oral carcinoma, and others), the opposite is true. PFN1 was downregulated in pancreatic cancer.19-20 Lower expression of PFN1 was significantly associated with a shorter survival period.20 In late-stage oral squamous cell carcinoma, PFN1 expression was lower than that in normal oral epithelium, and loss of PFN1 expression was related to invasion into and metastasis of lymph nodes.21 PFN1 was also decreased in late advanced hepatocellular carcinoma (HCC) and was associated with a poor survival rate of patients.22-23 In addition, PFN1 was found to be downregulated in nasopharyngeal carcinoma24 and breast cancer.25 Combined with another 4 actin-binding proteins, PFN1 could be used to construct a model for predicting poor prognosis of esophageal squamous cell carcinoma.26

Under normal physiological conditions, PFN1 is involved in multiple cellular functions, such as cell motility, migration, adhesion, and transduction signaling pathways.27 PFN1 is differentially expressed in various types of tissues and cells, which may explain its variable tumorigenic mechanisms in different tumors, even in different stages of the same cancer (Figure 2). Because PFN1 plays important roles in tumorigenesis and progression, targeting PFN1 dysregulation could to some extent influence the prognosis of patients with cancer. Determining the expression of PFN1 could thus be used to distinguish high-risk disease from lower-risk disease. Combination with other indices could further improve the diagnostic and prognostic value of PFN1.

In addition to dysregulation in tumor tissues, PFN1 was also found to bedifferentially expressed in the serum, urine, and extracellular vesicles of patients with cancer, which makes it possible to utilize PFN1 in liquid biopsy analysis of tumors. Compared with tumor tissue biopsy, liquid biopsy is a more practical method for real-time monitoring of patients with cancer.28 In addition, PFN1 was detected in the supernatants of cultured cells.

It has been shown that PFN1 gene expression is increased in peripheral blood cells of patients with HCC compared with healthy controls.29 A 9-gene expression system (including PFN1) was used to discriminate patients with HCC from healthy people.30 Proteomic analysis of serum proteins showed that PFN1 was increased in patients with gallbladder cancer. The expression difference between these patients and healthy controls was more than 2-fold.31 PFN1 was differentially expressed in the urine of patients with invasive and noninvasive bladder cancer. Further studies confirmed that PFN1 was notably decreased in the epithelium of invasive bladder tumors compared with noninvasive tumors, which was associated with the clinical outcomes of bladder cancer.32 In in vitro pancreatic cancer cell lines, PFN1 was downregulated in secretomes compared with nonneoplastic pancreatic ductal cells.33 In invitro cultured RCC cell lines, PFN1 was differentially regulated in the supernatant. Further studies revealed that PFN1 was upregulated in RCC tissues.34 Apart from its dysregulation in serum and urine, PFN1 was found to be downregulated in the circulating leukocytes of patients with breast cancer compared with healthy controls, which provides a new paradigm for highly sensitive and less invasive approaches for the diagnosis of breast cancer.35 Studies have already revealed that PFN1 can be secreted via exosomes or other secretory pathways.36-38

Extracellular PFN1 in the tumor microenvironment can be taken up by recipient cells and execute its function in recipient cells, which in turn may influence the biological behavior of cells in the microenvironment, ultimately affecting tumorigenesis and progression of cancers. As mentioned above, PFN1 is expressed differentially in the serum and urine of patients with cancer, which enables its application as a biomarker for diagnosis and prognosis in liquid biopsy (Table 1).

Cell motility involves membrane protrusion, cell matrix adhesion, cell body translocation, and rear detachment. Many of these processes require the actin cytoskeleton and its regulators. By facilitating the exchange of ATP for ADP on G-actin, PFN1 plays a major role in actin polymerization, thus influencing motility in numerous cells.39 PFN1 also participates in cell motility by regulating actin polymerization and interactions with other regulators of actin cytoskeletons, such as ARP3, VASP, and proteins of cell signaling pathways. Cell-cell adhesion and cell-matrix adhesion are critical contributors to maintaining tissue architecture. Dysregulation of cell-cell adhesion is an important sign in tumor initiation and progression of malignancy. PFN1 can modulate cell adhesion and epithelial-to-mesenchymal transition (EMT) in cancer cells. However, the mechanisms by which PFN1 regulates cell adhesion are still not very clear. Undoubtedly, learning more about the roles of PFN1 in cell adhesion and motility will help us better understand its roles in modulating tumor invasion and migration.

Since PFN1 plays a critical role in actin polymerization, it is an indispensable regulator of cell motility. PFN1 participates in the invasion and metastasis of multiple cancers. However, the roles of PFN1 in regulating cell motility are context specific.27 Exogenous PFN1 with intact actin-binding abilities can ameliorate the adherence and spreading capabilities of cancer cells and exert tumor-suppressive effects in breast cancer.40 Consistent with the results of the study by Wittenmayer et al, Zou et al found that PFN1 overexpression could revert MDA MB-231 cells to an epithelioid phenotype, with restored adherence junctions.41 In addition, PFN1 overexpression could promote AMPK activation and p27 phosphorylation, which in turn induces epithelial morphological reversion of mesenchymal breast cancer through restoration of adherens junctions.42 These studies highlighted the involvement of PFN1 in epithelial adhesion and differentiation, which helped us better understand its roles in cancer cell motility.

Invadopodia are actin-driven membrane protrusions that can deliver matrix metalloproteinases to degrade the matrix and support invasion and dissemination of tumor cells. Any dysregulation of the actin cytoskeleton can impair the formation and maturation of invadopodia.43-46 PFN1 can regulate PI(3,4)P2, which in turn negatively regulates lamellipodin at the leading edge of breast cancer cells and thus inhibits those cells motility.47 The depletion of PFN1 leads to an increase in the level of PI(3,4)P2 in invadopodia and its interacting adaptor Tks5. The interaction of PI(3,4)P2-Tks5 has been shown to promote the anchorage, maturation, and turnover of invadopodia, which in turn enhances the invasiveness and motility of breast cancer.48 Breast cancer is an invasive adenocarcinoma, and numerous studies have found that PFN1 is downregulated in breast cancer tissues.49-54 Overexpression of PFN1 reduces the invasion and migration of breast cancer cells, while loss of PFN1 significantly enhances breast cancer cell motility and invasion. Mechanisms involved in PFN1s negative roles in breast cancer metastasis include Enabled (Ena)/vasodilator stimulated phosphoprotein (VASP)-dependent lamellipodial protrusion,51 miRNA-182 regulation,52 and regulation of PFN1 degradation.53 Mouneimne et al found that PFN1 knockdown (KD) could increase F-actin bundles and enhance stress fiber formation. In that study, the numbers of protrusions in PFN1-KD cells were markedly decreased, and PFN1-KD could inhibit the motility of breast cancer.55 Moreover, Liu et al indicated that the interaction of LMO2-PFN1 and LMO2-ARP3 could promote the formation of lamellipodia/filopodia in basal-type breast cancer cells.56 Ena/VASP is a critical regulator of the actin cytoskeleton at the leading edge of cells, which controls membrane protrusions and cell motility. Cell-substrate adhesion and downregulation of Protein Kinase A (PKA) promote interactions of PFN1 with VASP, which is another mechanism by which PFN1 regulates cell motility.57-58 Knockdown of PFN-1 has been shown to abrogate the inhibitory effect of tyrphostin A9, suggesting that modulating PFN1 expression could have therapeutic potential in the treatment of metastatic breast cancer.59

As in breast cancer, PFN1 was found to be a suppressor of migration in HCC.22,23,60 All-trans retinoic acid60 and guttiferone K22 could inhibit hepatocellular cell migration and proliferation by upregulating the expression of PFN1. In prostate cancer, cathepsin X can inactivate PFN1, thus promoting adhesion, invasion, and migration of cancer cells.61 In CRC, elevated expression of PFN1 obviously inhibited invasion and migration. PFN1 was suppressed by the HLA-F-AS1/miRNA-330-3p/PFN1 or HCP5/miRNA-299-3p/PFN1/AKT axis.62-63

Interestingly, Ding et al showed that in the early stages of metastasis, breast cancer cells exhibit a hyperinvasive phenotype characterized by upregulation of MMP-9 and by faster invasion when PFN1 expression is downregulated. However, in the late stages of metastasis, loss of PFN1 markedly inhibits the growth of metastatic colonies of breast cancer cells.54 Rizwani et al reported that PFN1 expression was elevated in breast cancer tissues and that overexpression of PFN1 could inhibit the migration of breast cancer cells. The phosphorylation of S137 mutants abrogated PFN1s promotion of migration. These studies provided a different vision of PFN1s role in breast cancer metastasis.64

In gastric cancer, silencing PFN1 inhibited the invasion and migration of cells, and the PFN1 expression level in cancer tissue was positively correlated with tumor infiltration and lymph node metastasis.16 However, different conclusions were drawn from the study of Ma et al. The authors found that PFN1 expression was inversely correlated with lymph node metastasis.65 In the lung cancer cell line A549, downregulation of PFN1 inhibited migration.17 In addition, in vitro studies support the importance of PFN1 in the proliferation and migration of RCC cells, and treatment with a novel computationally designed PFN1-actin interaction inhibitor reduced the proliferation and migration of RCC cells in vitro and RCC tumor growth in vivo.13 Additional studies have demonstrated that downregulation of PFN1 can also suppress the migration of laryngeal cancer18 and bladder cancer.66

Although more studies on PFN1 have been completed recently, its roles in cancer metastasis are still unclear. The concentrations of actin and PFN1 are time- and space-specific, and so is the regulation of the actin cytoskeleton (Table 2). Additional thorough studies are needed to comprehend the mechanisms and laws regulating the actin cytoskeleton. More importantly, in addition to actin dependence, PFN1 affects cell migration in an actin-independent manner by interacting with proteins with PIP2 or PLP domains. Furthermore, lncRNAs and microRNAs also modulate the functions of PFN1. All of these proteins and RNAs interact with PFN1 and indirectly influence the functions of cancer cells, which makes understanding the roles of PFN1 in cancer metastasis and other functions more complicated (Table 3).

In yeast, the gene encoding PFN1 is essential for cytokinesis.67 Early studies revealed that PFN1/ embryos died as early as the 2-cell stage, while PFN1/+ embryos displayed reduced survival during embryogenesis compared with wild-type embryos; this indicates that PFN1 is essential for cell division and survival during embryogenesis.68 PFN1 silencing in endothelial cells inhibits proliferation.69 In addition, homozygous deletion of PFN1 in chondrocytes failed to complete abscission at late-stage cytokinesis.70 The results of all these studies imply that PFN1 plays a role in cell proliferation. In breast cancer, PFN1 overexpression (PFN1-OE) has been shown to inhibit cell growth and exert an inhibitory effect on tumorigenesis,25,40,52,71-75 and PFN1-OE suppresses the activation of AKT, which in turn inhibits the growth of tumor cells.71 PFN1-OE cells arrested at the G1 phase, which was partly attributed to the upregulation of P27kip1.72 miRNA-182 could downregulate PFN1 expression and promote triple-negative breast cancer cell proliferation.52 However, Yap et al put forward opposite views. The authors research results revealed that silencing PFN1 resulted in a multinucleation phenotype of breast cancer cells, thus inhibiting proliferation.76 Recent studies from Chakraborty et al also reported that PFN1 knockdown could upregulate SMAD3 and inhibit the proliferation of breast cancer.77 Results of single-cell studies on the extracellular matrix revealed that stiff extracellular matrix led to upregulation of PFN1, possibly promoting the proliferation of breast cancer.78 Apart from breast cancer, PFN1 was also found to suppress proliferation in pancreatic adenocarcinoma,20 endometrial cancer,79 and HCC.23,60 In gastric cancer, silencing PFN1 caused cell cycle arrest at G0/G1 phase, thus restraining cell proliferation.16 Knockdown of PFN1 could also inhibit the proliferation of laryngeal cancer.18 Our previous studies found that overexpression of PFN1 could promote the proliferation of multiple myeloma cells by accelerating the cell cycle from G1 to S phase.80 PFN1 is indispensable for cytokinesis. Nevertheless, PFN1 is involved in regulating cell proliferation not only by impacting cytokinesis but also by modulating cell cyclerelated proteins. Otherwise, PFN1 could also interact with cell signaling pathways and indirectly influence cell proliferation.

Tumor growth is not only about uncontrolled proliferation but also resistance to apoptosis.81 Actin dynamics have notable impacts on multiple stages of apoptosis.82 PFN1, as a critical actin-binding protein, is an indispensable regulator of actin dynamics, through which PFN1 participates in regulating apoptosis. PFN1 overexpression could upregulate the most common tumor-associated hotspot mutation of p53p53R273Hthus sensitizing cancer cells to apoptosis via the intrinsic apoptotic pathway.83 PFN1 has been shown to facilitate apoptosis of breast cancer cells, thus exerting a suppressive effect on tumorigenesis.73,75,83,84 By inducing apoptosis and reducing autophagy, PFN1 has also been shown to sensitize pancreatic cancer cells to irradiation. Additionally, overexpression of PFN1 can significantly elevate apoptotic markers such as cleaved caspase-3 and cleaved PARP after irradiation, suggesting that PFN1 can modulate radiosensitivity partly by regulating apoptosis.85

Given that PFN1 is involved in cell proliferation and apoptosis, it is not difficult to understand its roles in the drug resistance of tumor cells. PFN1 was found to be downregulated in butyrate-treated CRC cells,86 and proteomics studies revealed that PFN1 was differentially expressed in erinacine Atreated CRC cells,87 which suggested the roles of PFN1 in drug-mediated cell death and inhibition of proliferation. In addition, proteomics showed that PFN1 was differentially expressed in mitotane-treated adrenocortical carcinoma,88 and PFN1 was found to be increased in tocotrienol-treated MDA-MB-231 cells,89 indicating its roles in predicting the response to anticancer therapies. Compared with temozolomide (TMZ)-treated glioblastoma cells, PFN1 was downregulated in OKN-007 combined with TMZ-treated glioblastoma cells. Further study results revealed that PFN1 is involved in TMZ resistance.90 Results of our previous studies showed that PFN1 could interact with the Beclin 1 complex and participate in bortezomib resistance in multiple myeloma.80 Since PFN1 is involved in multiple cell processes, including proliferation, apoptosis, and proteomics, it was recognized as a biomarker for therapy sensitivity, and it is worth further exploring its roles in drug resistance. In addition, PFN1 was found to participate in angiogenesis,91-92 initiation of tumors,93 and autophagy.80 Loss of PFN1 in A549 cell lines resulted in fewer early apoptotic cells after treatment with piperlongumine, and PFN1 sensitized A549 cells to anticancer agents.17 PFN1 serves as a bridge for actin-cytoskeleton and cell signaling pathways and is involved in multiple biological and physiological processes. Dysregulation of PFN1 in cancer cells has a notable impact on sensitivity to chemotherapy or radiotherapy and may be a new target for the treatment of drug-resistant or radioresistant patients.

Studies have already confirmed that PFN1 is essential for cell survival in early embryos, as PFN1-KN could induce Drosophila embryos to die at the 2-cell stage.94 For further investigation of PFN1s roles in tissue-specific stem cells, Zheng et al established PFN1flox/flox mice that inducibly delete PFN1 in HSCs. Results showed that PFN1 was essential for the retention and metabolism of mouse hematopoietic stem cells in bone marrow partially through the axis of PFN1/G13/EGR1.95 These study results implied important roles of PFN1 in stem cell function, which were still unclear and deserved further research. Later study results have found that both overexpression and depletion of PFN1 could reduce the stem-like phenotype of MDA-MB-231 (MDA-231) triple-negative breast cancer cells, suggesting that a balanced expression of PFN1 was required for maintenance of optimal stemness and tumor-initiating ability of breast cancer cells.93 Considering that tumor heterogeneity is still an ongoing challenge for cancer treatment and that cancer stem cells (CSC) are considered to be a determining factor of tumor heterogeneity,96 intensive studies on PFN1s roles in CSC may provide us new insight into tumor initiation.

As mentioned above, PFN1 has been shown to be a critical participator of actin dynamics and to play important roles in cell migration. For cytotoxic T lymphocytes (CTLs), migration abilities are essential for patrolling tissues and locating targeted cells.97-98 Schoppmeyer et al thus studied PFN1s roles in CTL functions. The authors found that PFN1 negatively regulated CTL-mediated elimination of target cells and that PFN1 downregulation promoted CTL invasion into a 3D matrix in vitro. In patients with pancreatic cancer, PFN1 expression was substantially decreased in peripheral CD8+ T cells.99 However, considering the complexity of immune responses in vivo, the exact roles of PFN1 in tumor immunity remain unclear and need to be further explored.

Based on previous studies, we found that PFN1participates in multiple biological processes of tumor development and progression. Meanwhile, it is noteworthy that PFN1 plays opposite roles in different tumors and at different periods of tumor, potentially leading to the conclusion that PFN1s function in tumor has spatial and temporal specificity. Future studies on PFN1 should take this into account. PFN1 was shown to be of great significance for diagnosis and prognosis prediction and for monitoring the therapeutic effect of anticancer drugs, and PFN1s roles in tumor stemness and immunity may provide a new avenue for cancer therapy. Although much research has been done on PFN1 and cancer, puzzles still need to be solved. With deepening research, the function of PFN1 in cancer would be further clarified and its clinical value would be more prominent.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Conflicts of Interest: Authors declare no conflicts of interest for this article.

Acknowledgment: The authors are thankful for financial support from the Doctoral Fund Project of Hunan Provincial Peoples Hospital (program number BSJJ201812).

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