Paving the path for invasion: The polyedric role of LASP1 in cancer

Abstract

Although usually referred to as a structural actin-binding protein, LIM and SH3 domain-containing protein may actually be dynamically involved in the control of a wide spectrum of cellular processes, by virtue of its interaction with several molecular partners. Alongside being ubiquitously expressed in physiological conditions, LIM and SH3 domain-containing protein is overexpressed in a growing number of human cancers, in which it may actively contribute to their aggressiveness by promoting cell proliferation and migration. In view of the recent findings, implicating the protein in cancer progression, we discuss here the most relevant discoveries highlighting the role of this versatile protein in various human tumors. The correlation between LIM and SH3 domain-containing protein expression levels in cancer and the poor outcome and metastatic behavior of tumors denotes the clinical significance of this protein and hints its potential value as a new cancer prognostic or even diagnostic biomarker. This may be decisive not only to optimize existing pharmacological regimes but also to delineate novel, more efficacious therapeutic and/or preventive approaches.

Keywords

Cancer cell migration invasion metastasis microRNA

Introduction

Metastasis is a complex multistep process requiring the combination of many different cellular events. Cell detachment and migration, proteolysis of surrounding extracellular matrix (ECM), angiogenesis, and resistance to apoptosis are critical steps during cancer dissemination. Several secreted and cytosolic proteins, including not only matrix metalloproteinases (MMPs) and growth factors but also cytoskeletal proteins, act as key contributors in these processes.^1,2 LIM and SH3 domain-containing protein (LASP1) is predominantly involved in the reorganization of cytoskeleton during cellular motility^3,4 and localizes to cellular protrusions dedicated to migration such as lamellipodia, filipodia, pseudopodia, and invadopodia.^3–7 As other components of focal adhesions (FAs), including actin, vinculin, paxillin, and zyxin, in resting condition, LASP1 is assembled at the baso-lateral level of cellular membrane, where it regulates the anchorage of cells to ECM.⁷ These specific localizations are, at the same time, physiologically relevant during development and morphogenesis and extremely significant in cancer invasion and dissemination.³ As mentioned above, the loss of cellular adhesion, migration, and invasion are, in fact, decisive steps during cancer dissemination.^1,2

LASP1: a multi-domain polyhedral protein

LASP1 is a ubiquitously expressed protein classified as an actin-binding protein. However, its organization in specific domains is indicative of LASP1 implication in several cellular functions (Figure 1).³ The N-terminal portion is a LIM cysteine-rich domain composed of two zinc-finger residues, suggesting that LASP1 may interact with DNA and RNA. LIM domain is followed by two 35-residue nebulin-like segments, repeated in tandem, denominated, respectively, R1 and R2 domains conferring to LASP1 the ability to interact with cytoskeleton. R1/R2 domains are flanked by a phosphorylation motif (Ser-146 and Tyr-171) for cyclic adenosine monophosphate (cAMP)-dependent serine/threonine kinases including cAMP-dependent protein kinase (PKA), cGMP-dependent protein kinase (PKG), and cAbl. Moreover, the C-terminal is a SRC homology region 3 (SH3) domain; thus, it is plausible that LASP1 may also be able to interact with structural and signaling proteins.^3,4

Figure 1.

Schematic model of LASP1 domain structure. Functional domains and phosphorylation sites are shown. Known phosphorylation sites at serine 146 (S146) and tyrosine 171 (Y171) are marked with green boxes.

LASP1 and cancer: not just a bystander

As emerged from a still growing number of studies, LASP1 has been found to be upregulated in numerous different tumor entities, strongly associated with a poor clinical prognosis, including gallbladder cancer, human non-small-cell lung cancer (NSLC), colorectal cancer (CRC), ovarian and breast cancers, and choriocarcinoma (CC; Table 1).^{3,8,12,15,16,26,27} In this context, LASP1 appears to exert a driving role in regulating cancer cell metastatic propensity, probably perturbing the architecture and dynamics of FA, triggering cell migration, and invasion.⁹ As recently demonstrated by Li et al.,⁸ LASP1 overexpression correlates, in fact, with poor prognosis and metastasis in gallbladder cancer and its depletion arrests cell-cycle progression and migration in vitro and reduces the tumor mass in in vivo models of nude mice. Interestingly, these effects have been found, at least partly, mediated by downregulation of the calcium-binding protein S100P via the phosphoinositide 3-kinase (PI3K)/AKT pathway.⁸ Intriguingly, the same pathway has also been implicated in the pro-migratory effect of LASP1 in CRC cells through LASP1-mediated modulation of the tumor suppressor 14-3-3σ, an essential mechanism for CRC progression.⁹ Furthermore, it has been demonstrated that LASP1 induces transforming growth factor beta (TGFβ)-mediated epithelial–mesenchymal transition (EMT) by regulating S100A4 expression and promotes tumor progression both in vitro and in vivo.¹⁰ Recently, the analysis of regulatory mechanisms of LASP1-S100A11 axis identified flotillin-1 (FLOT1) and histone H1 as subcellular effectors, required for LASP1-S100A11-mediated EMT and CRC progression.¹¹ Overexpression of LASP1 was originally found in human breast cancer.^28,29 In particular, Bièche et al.²⁹ found that LASP1 levels are higher in patients clinically classified as human epidermal growth factor receptor 2 (HER2)/neu-positive. By means of structural analyses, Schulte et al.³¹ also found that LASP1 is fused with the pro-tumoral zinc-finger transcription factor TRPS1 in the ZR-75-30 breast cancer cell line. Moreover, in breast cancer cell lines BT-20 and MCF-7, it was observed that siRNA knockdown of LASP1 not only implicates a decrease in cell proliferation and migration in vitro but severely affects zyxin localization perturbing FA organization and impairing cell-ECM anchorage.¹² In addition, Grunewald et al.¹⁵ demonstrated LASP1 involvement in recruiting zyxin to focal contacts in in vitro models of ovarian cancer. In a recent study by Segerer et al.,¹⁶ an affection of migratory activities of CC cells after LASP1 silencing in CC was also demonstrated. Besides, in a recently published study, Endres et al.¹³ observed that LASP1 improves cell invasion both directly acting on cellular protrusions and indirectly by promoting the expression and secretion of MMP-1, -2, -3, and -9 in an in vitro setting using MDA-MB-231 breast cancer cell line. Even though the molecular mechanisms have not been pinpointed, authors first reported that LASP1 promotes MMP gene expression by indirectly regulating AP1 transcription factor. Of note, these effects, though at a minor extent, were also reported into bladder and prostate cancer cells expressing high levels of LASP1.¹³ Overexpression of LASP1 is also associated with poor overall survival in hepatocellular carcinoma (HCC) patients. In particular, it is correlated with poor prognosis for female and/or cirrhotic HCCs patients.^32,33 Intriguingly, the biological characterization of LASP1 expression in human HCC specimens led to the subdivision of patients in three groups in which LASP1 messenger RNA (mRNA) levels correlate with molecular and clinical features, representing a potential tool in the follow-up of patients and in the monitoring of disease progression from hepatic cirrhosis to HCC stage.¹⁸ Moreover, mass spectrometer analyses performed in HCC-derived cells led to the identification of vimentin (VIM) as a novel LASP1 molecular partner that, as authors hypothesized, could cooperate with LASP1 in cytoskeleton remodeling and, basically, in HCC cell migration.¹⁸ Recent data indicate that LASP1 is also implicated in malignant medulloblastoma dissemination¹⁹ as well as in hematological malignancies.²⁰ Concerning the last topic, the first evidence derived from a study performed by Friesch’s group indicates LASP1 involvement in chronic myeloid leukemia (CML) development. Importantly, the authors also proposed that the phosphorylation of LASP1 may be envisioned as an additional biomarker for assessment of BCR-ABL activity in CML.²⁰ Although performed in different experimental settings, overall, these studies concurrently highlight the primary and direct role of LASP1 in the migratory activity and consequently in cancer metastatic dissemination and progression by interacting with multiple binding partners, altering tumor microenvironment, and regulating transcriptional mechanisms.

Table 1.

LASP1 functions in different types of cancers.

Tumor entitity	Function of LASP1	References
Gallbladder cancer	Effect on proliferation and migration mediated by S100P regulation via the PI3K/AKT pathway.	Li et al.⁸
Colorectal cancer	Pro-migratory effect through 14-3-3σ modulation. EMT induction and tumor progression through interaction with S100A4, S100A11, FLOT1, and histone H1.	Shao et al.,⁹ Wang et al.,¹⁰ and Niu et al.¹¹
Breast cancer	Cell proliferation, migration, and anchorage to ECM. Cell invasion mediated by regulation of proteins of invadopodia and metalloproteinase expression. Chromatin remodeling through the CXCL12-dependent association with tUHRF1, DNMT1, G9a, and Snail.	Grunewald et al.,¹² Endres et al.,¹³ and Duvall-Noelle et al.¹⁴
Ovarian cancer	Cell proliferation and migration by zyxin regulation.	Grunewald et al.¹⁵
Choriocarcinoma	Proliferation and migratory activities in in vitro models.	Segerer et al.¹⁶
Bladder cancer	Regulatory effect on metalloproteinase expression. Oncogenic function.	Endres et al.¹³ and Duvall-Noelle et al.¹⁷
Prostate cancer	Regulatory effect on MMP expression.	Endres et al.¹³
Hepatocellular carcinoma	Cytoskeleton remodeling and migration involving interaction with vimentin.	Salvi et al.¹⁸
Medulloblastoma	Malignant tumor dissemination.	Traenka et al.¹⁹
Chronic myeloid leukemia	BCR-ABL target.	Frietsch et al.²⁰
Pancreatic cancer	Cancer progression and metastasis via HIF-1α.	Zhao et al.²¹ and Hao²²
Esophageal squamous cell carcinoma	Cell proliferation, invasiveness, metastasis, and progression.	Takeshita et al.²³ and Du et al.²⁴
Gastric cancer	Cell proliferation, migration, and invasion.	Wang et al.²⁵

LASP1: LIM and SH3 domain-containing protein; PI3K: phosphoinositide 3-kinase; EMT: epithelial–mesenchymal transition; ECM: extracellular matrix; CXCL12: C-X-C motif chemokine ligand 12; MMP: matrix metalloproteinase; HIF-1α: hypoxia-inducible factor 1 alpha.

LASP1: at the crossroads of post-transcriptional regulators

Given the close association between LASP1 overexpression and tumor aggressiveness, several studies focused on LASP1 regulation in order to identify mechanisms and molecules involved in its functions. Among LASP1 activators and inhibitors, hypoxia regulation, miRNAs expression, and histone methylation have been deeply investigated. Hypoxia is a condition featuring the microenvironment of several solid neoplasms and is associated to metastasis and poor prognosis. Fjeldbo et al.³⁴ identified LASP1 as a candidate reference gene for designing reverse transcription (RT)-quantitative polymerase chain reaction (qPCR) studies on hypoxia in squamous cervical cancer. It is already known that the hypoxia-inducible factor 1 alpha (HIF-1α) directly targets LASP1 in pancreatic cancer by binding its gene promoter and that this interaction significantly contributes to cancer progression and metastasis.²¹ Hao²² confirmed these results suggesting that HIF-1α targeting may effectively be used for treatment of this recalcitrant malignant disease. HIF-1α also regulates the expression of miR-210 in late stages of lung cancer.³⁵ Interestingly, miR-210, in turn, modulates HIF-1α activity, thanks to a positive-regulatory loop, thus mediating mitochondrial alterations and influencing cell metabolism and survival. Surprisingly, LASP1 has been listed among predicted genes downregulated following miR-201 overexpression in a lung adenocarcinoma cell line, thus suggesting the existence of a fine deep regulation of LASP1.³⁵ Indeed, the expression and the function of LASP1 are known to be influenced by several miRNAs and a growing body of evidence suggests their key role in regulating LASP1 oncogenic activity in a still increasing number of cancer types (Table 2). As a matter of fact, Zheng et al.²⁶ found that miR-203 regulates LASP1 expression in primary NSLC and miR-203 downregulation is coupled with the overexpression of LASP1 which correlates with tumor size, more advanced tumor–node–metastasis (TNM) stage, and lymph node metastasis. In regard to miR-203/LASP1, the above-mentioned experimental results have also been reported for high-risk prostate cancer³⁶ as well as for esophageal squamous cell carcinoma (ESCC).²³ Moreover, LASP1 expression inversely correlates with miR-1 in ESCC tissues where miR-1 trasfectants can directly downregulate LASP1.²⁴ Furthermore, it was reported that the downregulation of tumor-suppressive miR-1, miR-133a, and miR-218 enhances the metastatic potential of bladder cancer.¹⁷ Interestingly, LASP1 has been also proposed as an urinary biomarker for this kind of tumor.³⁸ A deregulation of tumor suppressor miR-1 was also associated with upregulation of LASP1 in metastatic CRC.³⁷ Furthermore, a recent paper indicates that miR-218 could inhibit the proliferation, migration, and invasion and promote apoptosis of gastric cancer cells by down-regulating LASP1 expression.²⁵ It is known that DNA methylation is a common feature of CRC and causes an aberrant expression of tumor-suppressive miRNAs through the hypermethylation of their promoters. Chen et al.³⁹ demonstrated that DNA hypermethylation is able to repress miR-1 and miR-133a expression in CRC, thus reducing the miRNA-associated repression of targeted genes. The same mechanism has been recently proposed for miR-145, which is able to suppress a number of oncogenes involved in cell-cycle distribution, growth, apoptosis, and angiogenesis. The authors demonstrated that miR-145 is able to directly suppress LASP1, reducing the invasiveness and the metastasis potential of CRC. Interestingly, they found that histone methylation may cooperate with binding of transcription factors on the core promoter regions in determining the level of miR-145, thus providing a novel mechanism of the upstream regulation of miR-145 expression and LASP1 activity in CRC cells.⁴⁰

Table 2.

List of microRNAs regulating LASP1 in different types of cancers.

MiRNAs	Tumor entity	References
MiR-203	Primary non-small-cell lung cancer Prostate cancer ESCC	Takeshita et al.,²³ Zheng et al.,²⁶ and Viticchie et al.³⁶
MiR-1	ESCC Bladder cancer Metastatic CRC	Chiyomaru et al.,¹⁷ Du et al.,²⁴ and Xu et al.³⁷
MiR-218	Bladder cancer Gastric cancer	Chiyomaru et al.¹⁷ and Wang et al.²⁵
MiR-133a	Bladder cancer	Chiyomaru et al.¹⁷

ESCC: esophageal squamous cell carcinoma; CRC: colorectal cancer.

LASP1: a new hub in cancer cell machinery

As detailed above, LASP1 is predominantly localized in the cytosol where it interacts with both resting and dynamic cytoskeletons as well as with actin-binding proteins such as zyxin, VASP, and LPP and with the tight junction protein zonula occludens 2 (ZO-2).⁷ However, experimental data indicate that LASP1 may also have a nuclear localization/translocation in cancer cells.^12,14,41 In breast cancer patients, the nuclear LASP1 (nLASP1) immunostaining seems to correlate with the overall survival suggesting that LASP1 may serve as a negative prognostic indicator and that unraveling the underlying molecular mechanisms may provide new key targets for treatment of specific subsets of breast cancer.⁴¹ Recently, it has been demonstrated that chemokines CXL12 and CXCL8 and the epidermal growth factor (EGF) and heregulin (HRG) trigger nuclear shuttling of LASP1 in human breast cancer.¹⁴ In addition, Mihlan et al. found that after a phosphorylation in Ser-146 mediated by PKA, LASP1 breaks its linkage with cytoskeleton reinforcing its binding with ZO-2 and as a dimer with ZO-2 moves to the nucleus. Conversely, LASP1 dephosphorylation on Ser-146, mediated by PP2B, makes this process of nucleo-cytoplasmic shuttling reversible.⁴² But, what is the significance of LASP1/ZO-2 translocation to the nucleus? As described above, LASP1 contains a LIM cysteine-rich domain composed of two zinc fingers, thus it conceivably binds directly with DNA, acting as transcriptional factors and/or regulator of target genes implicated in cell migratory activity. Moreover, the observed CXCL12-dependent association of nLASP1 with the epigenetic factors UHRF1, DNMT1, and G9a and the transcription factor Snail uncovered a novel role for nLASP1 in chromatin remodeling in human breast cancer.¹⁴ On the basis of these observations, LASP1 intriguingly appears to function as a hub for the epigenetic machinery of cancer cell.

Looking to the future: a new cancer biomarker?

Cancer dissemination is associated with intricate mechanisms where several molecular mediators seem to have a crucial role. The recent findings about LASP1 interactions with several partners involved in cancer progression highlight a novel role as a molecular hub as depicted in Figure 2. In this view, the urgency of identifying new targets and the discovery and validation of innovative therapeutic agents are quite reasonable. Although significant progress has been made in the treatment of tumors, currently, only few therapeutic protocols result effective for most of these diseases, while recent evidences highlight the impact of target therapy on the inhibition of cancer progression. The noticeable correlation between LASP1 overexpression in cancer along with the poor outcome and metastatic behavior of tumors definitely denotes the clinical significance of this protein and hints its potential value as a new cancer prognostic or even diagnostic biomarker. This may be decisive not only to optimize existing therapy regimes but also to delineate novel, more efficacious therapeutic and/or preventive approaches.

Figure 2.

LASP1 functions as polyhedral hub for the machinery of cancer cell. LASP1 actively contributes to tumor aggressiveness by promoting cell proliferation, metastasis dissemination, and chromatin remodeling through the direct and indirect interactions with several proteins. Moreover, LASP1 oncogenic activity is controlled by several miRNAs which, in turn, are modulated by HIF-1α. LASP1 interacting proteins are shown. The direct and indirect binding partners are indicated in deep pink and light blue, respectively.

Footnotes

Acknowledgements

The authors are grateful to Dr Pellegrino Musto who endorsed this work. V.R. and F.A. contributed equally to this work.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a grant from Italian Ministry of Health (Ricerca Corrente to IRCCS-CROB).

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