TLN1: an oncogene associated with tumorigenesis and progression

Abstract

Talin-1 (TLN1), encoded by the TLN1 gene, is a focal adhesion-related protein capable of binding various proteins in the cytoskeleton. It is also expressed at high levels in many cancers wherein it influences cellular adhesion and the activation of integrins. TLN1 is also capable of promoting tumor cell invasivity, proliferation, and metastatic progression, in addition to being a relevant biomarker and therapeutic target in certain cancers. The present review offers a comprehensive overview of current knowledge regarding TLN1 with respect to its structural properties, functions, and role in tumor development.

Introduction

Globally, cancer continues to be a leading cause of death and morbidity, with an estimated 1 in 8 males and 1 in 10 females facing cancer in their lifetime even in countries with a low human development index. Indeed, cancer is one of the deadliest diseases such that it is potentially the largest barrier to improvements in human life expectancy throughout the world [1]. Talin-1 (TLN1) is an essential cytoskeletal protein of 270 kDa that regulates integrin activation and mediates binding interactions between actin and integrins [2–5]. While TLN1 expression levels vary across tumor types (Fig. 1), it differs significantly from the levels observed in normal tissues in 12 tumor types in the GEPIA database (Fig. 2). High levels of TLN1 expression have the potential to drive enhanced invasivity and migration in cancers including glioblastoma, nasopharyngeal carcinoma, and prostate cancer, whereas it can have the opposite impact in hepatocellular carcinoma [6–10]. In one report, miR-1303 was found to drive liver cancer cell proliferative, invasive, and metastatic activity via promoting TLN1 downregulation, thereby inhibiting apoptotic cell death [11]. This review provides a summary of the structural and functional characteristics of TLN1 together with an overview of current research progress focused on the role of TLN1 in a range of malignancies, including its effects on tumor cell behavior and the underlying molecular mechanisms.

Fig. 1.

The TLN1 expression profile was determined from the GEPIA database based on tumor samples and paired normal tissues, retrieved on November 28, 2023. The figure encompassed various cancer types, including Adrenocortical Carcinoma (ACC), Breast Invasive Carcinoma (BRCA), Cholangiocarcinoma (CHOL), Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (DLBC), Glioblastoma Multiforme (GBM), Kidney Chromophobe (KICH), Kidney Renal Papillary Cell Carcinoma (KIRP), Brain Lower Grade Glioma (LGG), Lung Adenocarcinoma (LUAD), Ovarian Serous Cystadenocarcinoma (OV), Pheochromocytoma and Paraganglioma (PCPG), Rectum Adenocarcinoma (READ), Skin Cutaneous Melanoma (SKCM), Testicular Germ Cell Tumors (TGCT), Thymoma (THYM), and Uterine Carcinosarcoma (UCS)

Fig. 2.

On November 28, 2023, GEPIA database analysis revealed significant differences in TLN1 expression between twelve tumor samples and their paired normal tissues. TLN1 gene expression is lower in BLCA (bladder urothelial carcinoma) tumor samples (n = 404) compared to paired normal tissues (n = 28), with P ≤ 0.05 A. TLN1 gene expression is lower in CESC (Cervical squamous cell carcinoma and endocervical adenocarcinoma) tumor samples (n = 306) compared to paired normal tissues (n = 13), with P ≤ 0.05 B. TLN1 gene expression is higher in CHOL (cholangio carcinoma) tumor samples (n = 36) compared to paired normal tissues (n = 9), with P ≤ 0.05 C. TLN1 gene expression is lower in COAD (colon adenocarcinoma) tumor samples (n = 275) compared to paired normal tissues (n = 349), with P ≤ 0.05 D. TLN1 gene expression is higher in GBM (glioblastoma multiforme) tumor samples (n = 163) compared to paired normal tissues (n = 207), with P ≤ 0.05 E. TLN1 gene expression is higher in LGG (brain lower grade glioma) tumor samples (n = 518) compared to paired normal tissues (n = 207), with P ≤ 0.05 F. TLN1 gene expression is lower in LUAD (lung adenocarcinoma) tumor samples (n = 483) compared to paired normal tissues (n = 347), with P ≤ 0.05 G. TLN1 gene expression is lower in LUSC (lung squamous cell carcinoma) tumor samples (n = 486) compared to paired normal tissues (n = 338), with P ≤ 0.05 H. TLN1 gene expression is higher in PAAD (pancreatic adenocarcinoma) tumor samples (n = 179) compared to paired normal tissues (n = 171), with P ≤ 0.05 I. TLN1 gene expression is lower in READ (rectum adenocarcinoma) tumor samples (n = 92) compared to paired normal tissues (n = 318), with P ≤ 0.05 J. TLN1 gene expression is lower in UCEC (uterine corpus endometrial carcinoma) tumor samples (n = 174) compared to paired normal tissues (n = 91), with P ≤ 0.05 K. TLN1 gene expression is lower in UCS (uterine carcinosarcoma) tumor samples (n = 57) compared to paired normal tissues (n = 78), with P ≤ 0.05 L. In the figure, statistically significant data are indicated by an asterisk in red (P ≤ 0.05)

The structural characteristics of TLN1

As a FERM domain protein family member, TLN1 is a 2,541 amino acid protein weight 270 kDa [12]. TLN1 consists of an N-terminal globular head region that contains a linear FERM domain as well as a C-terminal rod domain with 13 subdomains (R1-R13), harboring three F-actin binding sites, a site for integrin binding, a dimerization domain, and multiple RIAM and Vinculin binding sites [13, 14]. TLN1 includes a C-terminal I/LWEQ module capable of interacting with F-actin [15–17], facilitating the targeting of this protein to focal adhesion sites [18]. The FERM domain consists of four subdomains (F0-F1-F2-F3), among which the main integrin-binding site (IBS) is located in the F3 subdomain and is capable of interacting with conserved NPXY motifs within the tail domains of β-integrins [19–21]. Interactions between the R9 and F2F3 subdomains of TLN1 within quiescent leukocytes result in the masking of the primary IBS such that the protein remains in an auto-inhibited state [22]. The modular construction of TLN1 enables it to engage in several different functions, the N-terminal FERM domain participating in the regulation of integrin activation, whereas the R-helical rod domain harbors a minimum of three sites capable of interacting with vinculin, a component of focal adhesions [23]. TLN1 is ultimately predicted to form a structure composed of 62 α-helices linked by a series of short unstructured regions [24].

The function of TLN1 in normal cells

TLN1-mediated regulation of integrin activation

At baseline, integrin expression is generally restricted to low-affinity forms until agonistic signals initiate signal transduction cascades within integrin-expressing cells through various receptors, thereby triggering the production of high-affinity integrins through a process referred to as integrin activation [25]. Integrins serve as essential receptors involved in the processes of extracellular matrix assembly, cellular adhesion, and migration [26]. The functions of these proteins are closely tied to the regulation of their ligand affinity [25]. Such regulation is achieved owing to the fact that integrins can adopt various conformations including a low-affinity closed, bent conformation, an intermediate-affinity conformation with partial extension but a closed headpiece, and a high-affinity open conformation that is fully extended [27, 28]. Binding between the head domain of TLN1 and β integrin subunit NPXY motifs can drive these integrins to transition from a low-affinity closed state to an intermediate-affinity state, while a second interaction between TLN1 and β tail membrane-proximal region can further promote the interacting β integrin to adopt a high-affinity conformation [19]. The induction and maintenance of high-affinity integrity activity requires the effects of both talins and kindlins [29], which spur higher levels of transition from low- to high-affinity states [27]. Bromberger et al. [30] determined that the direct Rap1/TLN1 interaction plays a critical role in regulating integrin types expressed by neutrophils and platelets, both of which require dynamic, rapid integrin-mediated responses. Gao et al. [31] determined that integrin αIIbβ3 activation on platelets can be enhanced by cooperative interactions between members of the PXN family and kindlin and talin proteins. In a series of ex vivo flow adhesion studies and in vivo research focused on the adhesion of platelets to injured arterial walls, Nieswandt et al. [32] determined that IIb β3 integrin and β1 integrin activation can be disrupted by a loss of talin. Haling et al. [33] additionally determined that while talin-integrin MPR interactions are vital for agonist-induced platelet integrin activation, they also serve an essential function in the context of platelet fibrin clot retraction. Gingras et al. [25] further posited that a Rap1 binding site and a temporary lipid-dependent helix in the F1 domain collaborate to facilitate Rap1-TLN1 interactions and integrin activation.

TLN1 as a regulator of focal adhesions

Focal adhesions (FAs) are complexes that form through processes that include integrin clustering, actin bundling, and the enhancement of these interactions to produce mature structures that enable interactions between cells and the ECM [34]. FAs are vital for the elongation of endothelial cells (ECs) and the formation of linear cell–cell junctions. In the absence of normal endothelial integrin signaling, these processes are disrupted such that vessel beds are compromised, potentially contributing to vascular leakage and hemorrhaging [35]. Talins serve as vital mediators of the formation of FAs, the attachment of actin, and FA maturation [36, 37]. TLN1 is also essential for the recruitment of vinculin and the formation of mature FAs [37, 38]. Chau et al. [35] provided clear evidence for the inability of vinculin-positive FAs to form in the context of TLN1 deficiency, while also underscoring the importance of FAs in the context of vascular remodeling. As TLN1 is the major factor that links the cytoplasmic tail of β-integrins to the actin cytoskeleton [39–41], it is a critical mediator of FA formation [42]. The TLN1 C-terminal I/LWEQ module is capable of specifying F-actin binding [43], and this conserved module is essential for the ability of TLN1 to bind to FAs [18, 44]. TLN1 constructs harboring binding sites for FA components including integrins, FAK, and vinculin but lacking this I/LWEQ module do not properly target to FAs [44]. The C-terminal ABS3 site is situated within the dimeric R13-DD double domain [45], wherein it serves as a key regulator of FA assembly [46]. FAs can be stabilized by VBS and vinculin binding to talin [47, 48]. Vigouroux et al. [49] determined that actomyosin force propagates mechanosensitive transitions that link newly formed adhesions and FAs that the regulation of talin binding by vinculin and RIAM.

TLN1 autoinhibitory properties

TLN1 primarily exists in the cytosol in an autoinhibited form, with interactions between the rod and head domains of a given TLN1 molecule ultimately masking the IBS and the plasma membrane association site within the rod domain [50–52]. This autoinhibitory confirmation can be adopted owing to interactions between the N-terminal F3 FERM domain and residues of 1655–1822 of the C-terminal domain, thereby blocking the IBS within the F3 domain [51, 52]. Haage et al. [53] concluded that such autoinhibition can suppress the functionality of TLN1, thereby shaping integrin-mediated cellular adhesion to the ECM in vivo. Cryoelectron microscopy studies of autoinhibited recombinant TLN1 further revealed charge-based interactions among the 13 rod domains of the TLN1 monomer, resulting in the entanglement of this protein in a highly compact globular structure 15 nm in size secured by F2 and F3 FERM subdomain interactions with the R12 and R9 rod domains. As a result, the R12 domain fully blocks the PIP2 binding site in the FERM domain such that binding to the plasma membrane cannot occur. The IBS is situated deep within the autoinhibitory pocket such that the protein is unable to bind vinculin or to engage in actin binding site 2 (ABS2)-mediated actin binding, although this conformation does not result in the occlusion of the ABS3 site for actin binding [22].

The crosstalk between TLN1 and collagen receptor

Capillary morphogenetic gene 2 (CMG2), or anthrax toxin receptor 2 (ANTXR2), is a protein involved in cancer progression, genetic diseases, pulmonary hypertension, and angiogenesis [54–58]. It acts as a receptor for collagen VI in the extracellular matrix [59]. Mutations in the ANTXR2 gene cause hyaline fibroma syndrome (HFS) [60, 61], a rare autosomal recessive disorder marked by abnormal hyaline deposits in connective tissue. Mutations in the ANTXR2 gene cause the growth of hyaline fibrous tissue, leading to two forms of HFS: the more severe infantile systemic hyaline syndrome (ISH) and the less severe juvenile hyaline fibromatosis. ISH often results in premature death due to widespread systemic effects. Bürgi et al. [62]. Explored how the collagen VI receptor CMG2 interacts with the actin cytoskeleton. They found that without a ligand, CMG2 binds to actin through tallin and vinculin. When a ligand binds, CMG2 releases tallin and binds to RhoA instead. This switch is crucial for regulating collagen VI levels, as mutations in CMG2 that prevent this switch lead to extracellular matrix buildup seen in HFS patients.

The function of TLN1 in cancers

The role of TLN1 in hematologic neoplasms

Chronic myeloid leukemia (CML) is a cancer that is driven by a BCR-ABL1 kinase fusion resulting from the (9;22) chromosomal translocation. While many CML cases can be treated through the use of tyrosine kinase inhibitors (TKIs), TKI resistance can emerge in some cases [63]. EVI1 overexpression in CML-blast crisis cells is indicative of a higher risk of disease recurrence and resistance to TKIs [64]. TLN1 is an essential mediator of EC-related angiogenesis, and it is also believed to contribute to abnormal malignant B cell metastasis to the lymph nodes and bone marrow in CML and multiple myeloma patients [65, 66]. Abnormal trafficking can lead to drug resistance mediated by cell adhesion [66]. Halder et al. [63] determined that EVI1 is capable of targeting TLN1 at the transcriptional level, leading to its upregulation in CML, with this relationship having important implications for drug resistance and CML progression [63]. EVI1 overexpression in CML-blast crisis cells and its relationship with resistance to TKIs is noteworthy, emphasizing the need to better study the mechanisms that govern drug resistance in CML. Efforts to better clarify how EVI1 functions to regulate TLN1 transcription will yield further insights that may aid in the more effective treatment of CML.

Myeloid leukemia (AML) is a particularly aggressive hematological cancer that is associated with substantial treatment resistance and recurrence risks [67]. AML patients generally present with poor overall survival and other outcomes [68]. A majority of individuals with AML present with TLN1 upregulation [69], and Cui et al. [69] determined that TLN1 serves as a valuable prognostic biomarker and indicator of immunological infiltration in individuals with AML, impacting disease progression through the regulation of cell cycle activity, differentiation, proliferative activity, and apoptotic cell death, while also regulating several associated signaling pathways.

Reproductive system cancers

Ovarian serous carcinoma (OSC) accounts for 68% of all ovarian cancer diagnoses and an estimated 88% of all stage III and IV cases [70]. The expression of TLN1 has been demonstrated to independently predict poorer OSC patient survival such that it may be associated with aggressive activity in these tumors [71]. The expression of TLN1 in OSC tumors is significantly upregulated, particularly in the context of metastatic tumors, and it is closely associated with the onset and metastatic progression of this cancer type [72]. In a rat OSC model, serum TLN1 levels were increased during both early and advanced disease, consistent with its role as a regulator of OSC development [73]. Tang et al. [72] osited that miR-9 overexpression can lead to TLN1 downregulation and the consequent inhibition of FAK/AKT signaling activity mediated by TLN1, thus inhibiting invasivity, migration, and proliferative activity in OSC (Fig. 3). Chan et al. [74] etermined that upregulation of miR-378 in OSC cells altered TLN1 expression.

Fig. 3.

The role of TLN1 in cancers. Phosphorylation of talin1 mediated by CDK5 results in β1 integrin activation to promote PCa bone metastasis, and miR-9 may mediate the suppression of TLN1 expression by inhibiting the activation of the TLN1-regulated FAK/AKT signaling pathway to inhibit the proliferation, migration and invasion of tumor; TLN1 can be recognized as a biomarker, prognostic marker and therapeutic target in tumors; miR-1303 drives cancer cells proliferative, invasive, and metastatic activity via regulating TLN1, while miR-429 and circRNA_400029 impair proliferative, invasive, and metastatic activity of cancer cells through the regulation of TLN1. In the picture, the red plus sign represents facilitation and the red minus sign represents inhibition

As the second most frequently diagnosed gynecological malignancy, cervical cancer (CC) is increasingly being diagnosed among individuals of younger age [75]. In one report, circRNA_400029 and miR-1285-3p were reported to control TLN1 expression, thus regulating proliferative, migratory, and invasive activity in CC [76] (Fig. 3).

In developed nations, endometrial cancer remains the most common gynecological malignancy. Next-generation sequencing has important implications for the design of anticancer drugs [77] and targeted therapeutics [78]. Chang et al. [79]. Analyzed 14 tumor samples from endometrial cancer patients in Taiwan and identified 21 putative passenger genes, among which was included TLN1.

Neoplasms of the digestive system

Liver cancer is the third most deadly form of cancer worldwide, and the second most deadly in China [80], with the lack of effective therapeutic options contributing to the poor survival outcomes for affected patients [81, 82]. Due to its low expression levels in liver cancers and partial reversal of miR-1303's effects, TLN1 is likely to suppress the pathogenesis of liver cancer [11]. Huang et al. [11] speculated that miR-1303 is able to drive enhanced liver cancer cell migration, proliferation, and invasivity owing to its ability to target TLN1 and consequently suppress apoptosis (Fig. 3).

Gastric cancer (GC) is highly prevalent, ranking as the fourth most common malignancy [83]. Huang et al [84] reported a significant link between TLN1 and GC risk. In another report, authors additionally determined that TLN1 levels in GC tumors are significantly elevated, with TLN1 augmenting the ability of these cells to invade and migrate via the PTK2-PXN-VCL-E-Cadherin-CAPN2-MAPK1 pathway [85].

Colorectal cancer (CRC) is a solid tumor type that is common among both men and women [86, 87], ranking as the third in terms of commonness and second in terms of mortality in tumors [1]. In CRC cells, TLN1 has been found to drive the enhancement of proliferative activity, angiogenesis, and adhesion [88], while also being associated with the aggressiveness of these cells [89] and contributing to enhanced circulating tumor cell (CTC) extravasation and metastatic dissemination [90]. Concentrations of TLN1 are related to TNM staging, tumor sizing, and lymph node metastatic progression [88]. Yang et al. [91] additionally observed a positive association between TLN1 and the metastasis of CRC to the liver. By detecting TLN1 mRNA expression in 77 fresh samples of CRC, Vafaei et al. [89] found that low TLN1 mRNA expression accounted for 9%, 29.9%, 24.7%, and 19.5% of stage I, II, III, and IV CRC, respectively. An analysis of these data using Pearson’s χ2 test revealed a statistically significant correlation between TLN1 mRNA expression level and TNM stage (P = 0.034), and this suggested that TLN1 expression was associated with TNM stage. TLN1 protein levels have been suggested to offer utility as a new biomarker for CRC detection [88]. Zhang et al. [92] also proposed the value of TLN1 as a prognostic target in CRC and a viable marker for the targeted treatment of this cancer type. The above studies indicate that TLN1 is of great research value in CRC, but there is no research here to prove how TLN1 affects the occurrence and development of CRC.

Cancers of the nervous system

Gliomas present with very high mortality rates and contribute to an estimated 15,000 deaths annually in the USA [93]. You et al. [94] determined that TLN1 overexpression was sufficient to enhance glioma cell invasivity, migratory activity, viability, and expression of vimentin, MMP-9, and cyclin D1. Moreover, Sen et al. [95] determined that TLN1 serves as a contributor to glioma cell motility and spread. Through its ability to regulate the miR-16-5p/TLN1 pathway, tanshinone IIA has been demonstrated to function as an inhibitor of glioma cell proliferative, invasive, and migratory activity [94]. High-grade glioma (glioblastoma) patients present with a median 15–16 month survival period [93], and Sen et al. [95] suggested that TLN1 depletion in glioblastoma can lead to a reduction in traction forces and the ability of these cells to migrate. In line with this suggestion, de Semir et al. [96] demonstrated the ability of TLN1 and ZYX to serve as partial mediators of the ability of pleckstrin homology domain interacting protein to contribute to invasion and migration. Tumors of the brain are the deadliest solid tumor type in children, and ~ 80% of cases are of the diffuse intrinsic pontine glioma (DIPG) type. Saratsis et al. [97] demonstrated through Western immunoblotting and immunohistochemistry that TLN1 is specifically upregulated in DIPG lesions but not in normal brainstem tissues surrounding these lesions.

Cancers of the respiratory system

As of 2018, lung cancer was the most common and deadliest cancer with 2.1 million diagnoses and 1.7 million deaths [98].of these cases, ~ 85% are of the deadly non-small cell lung cancer (NSCLC) subtype [99], with most patients exhibiting advanced disease facing poor prognostic outcomes [100]. Since the disease does not often manifest some specific symptoms at the onset, it is often diagnosed when it has reached an advanced stage. Wu et al. [101] demonstrated a potential link between mutations in TLN1 and the metastasis of NSCLC such that it may represent a biomarker and/or target for treatment. By employing an SRM/SIS approach, Novikova et al. [102] additionally determined that detecting TLN1 in the blood can aid in tumor detection, with its upregulation in combination with the detection of PACSIN2 helping to distinguish between lung tumors and other forms of cancer.

Nasopharyngeal carcinoma (NPC) cases are relatively common at the global level, but they affect upwards of 20–50 per 100,000 persons annually in Southeast Asia and South China [103–106]. NPC cells and tissue samples exhibit TLN1 upregulation, and the knockdown of this gene can compromise the ability of these cells to migrate and engage in invasive behaviors [6]. Through its ability to downregulate TLN1, miR-429 was identified as an inhibitor of NPC cell invasivity, migratory activity, and proliferation, albeit through an indirect regulatory relationship [107] (Fig. 3). Xu et al. [6] determined that higher TLN1 levels were tied to the worse overall and distant metastasis-free survival of individuals with NPC such that it may be useful as a prognostic indicator.

Oral cancer cases are the sixth most prevalent at the global level [108, 109], with oral squamous cell carcinoma (OSCC) tumors emerging through the accumulation of multiple abnormal characteristics [110]. TLN1 upregulation has been noted in OSCC, particularly in tissues invaded by OSCC cells, with TLN1 knockdown suppressing the adhesion, migratory activity, growth, and invasivity of OSCC [111, 112]. Lai et al. [112] observed that TLN1 overexpression was associated with greater OSCC tumor aggression, and such overexpression was identified as an adverse prognostic indicator in OSCC patients.

Cervicothoracic cancers

Breast cancers exhibit substantial heterogeneity such that they are categorized based on clinical, histological, and gene expression features [113]. Triple-negative breast cancer (TNBC), The most deadly type of breast cancer, lacks HER2 amplification or hormone receptor expression, and accounts for 15–20% of all patients with breast cancer [114, 115]. TNBC tumors typically exhibit significant TLN1 upregulation that is related to worse prognostic outcomes, with TLN1 binding to integrin β1 contributing to greater tumor malignancy and metastatic potential such that silencing TLN1 can suppress TNBC tumor growth, adhesion, and metastatic progression [116]. Ashaie et al. [117] determined that siRNA-mediated TLN1 knockdown was sufficient to reduce the burden of breast cancer, and Singel et al. [118] determined that the chemosensitivity of four TNBC cell lines (HCC1937, MDA-MB-231, Hs478T, HCC38) can be enhanced by knocking down TLN1. Zhang et al. [116] observed that TC67399 is capable of blocking TLN1 binding interactions with integrin β1, thereby repressing TNBC cell metastatic potential.

Urologic neoplasms

Worldwide, prostate cancer (PCa) is the second common malignancy among males [119], and TLN1 has been demonstrated to serve as a promoter of PCa cell metastasis and migration [10]. Zhang et al. [120] demonstrated that miR-124 is capable of impairing PCa cell adhesion, invasivity, and migratory activity through its ability to suppress the expression of TLN1. Jin et al. [7] further revealed that CDK5-mediated TLN1 phosphorylation can favor the bone metastasis of PCa tumors as a result of the activation of β1 integrin (Fig. 3), while also enhancing PCa cell invasivity, migration, and anoikis resistance. The observed TLN1 upregulation reported by Xu et al. [121] was posited to be associated with the malignancy of PCa tumors and their metastasis to the lymph nodes, with a combination of elevated TLN1 levels and a Gleason score > 7 aiding in the prediction of PCa tumor lymph node metastasis. O’Rourke et al. [122] also provided evidence that autoantibodies directed against TLN1 are indicative of PCa, with an area under the curve value of 91.1% (sensitivity: 80.5%, specificity: 80%).

Other tumor types

Osteosarcoma (OSA) is the most commonly diagnosed form of primary bone tumor, primarily impacting children and adolescents with approximately 5.6 cases per million each year in individuals less than 15 years of age [123–126]. Van et al. [127] observed the inhibited motility of the OSA U2OS cell line when using a siRNA specific for RUNX2 or TLN1. While RUNX2 regulates adhesion- and motility-related gene expression, it fails to influence the expression of TLN1 within OSA cells.

Discussion

TLN1 is a 270 kDa cytoskeletal protein that is closely related to integrin activation and the formation of links between actin and integrins [2–5]. Of the four FERM subdomains present in TLN1, the IBS is present within the F3 domain and is capable of interacting with the conserved NPXY motif present in the tail domains of β integrins near the plasma membrane [19–21]. Integrins are vital for effective adhesion, migratory activity, and ECM assembly [26], while TLN1 plays a key role in integrin activation [128–130]. TLN1 autoinhibition can modulate its function, thereby playing a key role in regulating several facets of in vivo integrin-mediated adhesion to the ECM [53]. FAs are vital for the formation of linear cell–cell junctions and the elongation of ECs [35], with the potential for negative outcomes when these processes are disrupted. TLN1 serves as a key factor for the recruitment of vinculin and for mature FA formation [37, 38]. When the STRING database was employed to identify potential factors capable of interacting with TLN1, these proteins included Vinculin (VCL), Paxillin (PXN), Zyxin (ZYX), FA kinase 1 (PTK2), Proto-oncogene tyrosine-protein kinase Src (SRC), Amyloid beta A4 precursor protein-binding family B member 1-interacting protein (APBB1IP), Integrin β-1 (ITGB1), Integrin β-3 (ITGB3), Phosphatidylinositol 4-phosphate 5-kinase type-1 gamma (PIP5K1C), and Filamin-A (FLNA) (Fig. 4).

Fig. 4.

TLN1 interacts with 10 predicted proteins from the STRING online website (version 12.0), acquired on November 28, 2023. Vinculin (VCL), Paxillin (PXN), Zyxin (ZYX), Focal adhesion kinase 1 (PTK2), Proto-oncogene tyrosine-protein kinase Src (SRC), Amyloid beta A4 precursor protein-binding family B member 1-interacting protein (APBB1IP), Integrin beta-1 (ITGB1), Integrin beta-3 (ITGB3), Phosphatidylinositol 4-phosphate 5-kinase type-1 gamma (PIP5K1C), Filamin-A (FLNA)

The functions of TLN1 detailed above are highly important, and it also serves as an important regulator of the incidence and progression of many tumor types (Table 1). High TLN1 levels have been demonstrated to contribute to enhanced invasivity and migration in many malignancies, including glioblastoma, PCa, and NPC, although it the opposite effect has been reported in hepatocellular carcinoma [6–10]. Many reports have shown the utility of TLN1 as a prognostic or diagnostic biomarker and/or as a target for therapeutic intervention (Fig. 3), further underscoring its relevance to diagnosing, monitoring, and treating cancer patients. Current literature indicates that TLN1 is expressed at low levels in liver cancer and CRC (Table 1). Reduced TLN1 expression enhances invasion and metastasis in both cancers and is linked to liver metastasis, TNM stage, and lymph node metastasis in CRC [9, 88, 89]. Interestingly, both high and low TLN1 expression appear to promote cancer progression, making it a noteworthy topic for further discussion.

Table 1.

the expression, signaling pathway and function of TLN1 in different tumors

Tumor type	Cell Line	Expression in tumor	Signaling pathways/effectors	Inference	Potential biomarker (under study)	Reference
Chronic myeloid leukemia (CML)	–	–	–	EVI1 is capable of targeting TLN1 at the transcriptional level, leading to its upregulation in CML, with this relationship having important implications for drug resistance and CML progression	–	[63]
Acute myeloid leukemia (AML)	KG-1 MOLM13 Kasumin-1 K562 THP-1 HL60	↑	–	TLN1 impacts AML progression through the regulation of cell cycle activity, differentiation, proliferative activity, and apoptotic cell death, while also regulating several associated signaling pathways	A prognostic marker and marker of immune infiltration for AML patients	[69]
Ovarian serous carcinoma (OSC)	SKOV3 CAOV3 OVCAR3	↑	MiR-9 and FAK/AKT signaling pathway	Connected with aggressive activity in OSC MiR-9 overexpression can lead to TLN1 downregulation and the consequent inhibition of FAK/AKT signaling activity mediated by TLN1, thus inhibiting invasivity, migration, and proliferative activity in OSC	An independent indicator of poor survival A promising predictor of aggressiveness	[71, 72]
Cervical cancer (CC)	SiHa HeLa CaSki C-33A	↑	CircRNA_400029 and miR-1285-3p	CircRNA_400029 and miR-1285-3p can control TLN1 expression, thus regulating proliferative, migratory, and invasive activity in CC	–	[76]
Endometrial cancer	–	–	–	Be considered as a passenger gene in 14 tumor samples from endometrial cancer patients in Taiwan	A passenger gene	[79]
Liver cancer	Huh-7 MHCC97-H HepG2	↓ ↓ ↓	MiR-1303	MiR-1303 is able to drive enhanced liver cancer cell migration, proliferation, and invasivity owing to its ability to target TLN1 and consequently suppress apoptosis The role of MiR-1303 is partially reversed in liver cancer by TLN1	–	[11]
Gastric cancer (GC)	MKN-45	↑	PTK2-PXN-VCL-E-Cadherin-CAPN2-MAPK1 signaling axis	TLN1 is significantly related to risk of GC TLN1 promotes the ability of GC cells to invade and migrate via the PTK2-PXN-VCL-E-Cadherin-CAPN2-MAPK1 pathway	–	[84, 85]
Colorectal cancer (CRC)	–	↓	–	Talin1 may promote proliferation, adhesion, angiogenesis of colon cancer cell, be related to CRC aggressiveness and boost the extravasation and metastasis of colon cancer circulating tumor cells (CTCs) Associated with hepatic metastatic CRC Low level mRNA expression of talin1 is connected with increases in TNM stages	A novel biomarker to detect colon cancer One of prognostic CRC markers and a valid indicator of the clinical and targeted therapy of CRC	[88–92]
Gliomas	T98G A172 U373 MG	↑ ↑ –	Tanshinone IIA	TLN1 overexpression was sufficient to enhance glioma cell invasivity, migratory activity, viability, and expression of vimentin, MMP-9, and cyclin D1 Tanshinone IIA inhibits glioma cell proliferative, invasive, and migratory activities Depletion of TLN in glioblastoma generates diminished traction forces and migratory capability TLN1 and ZYX in glioblastoma mediate at least in part the proinvasive and promigratory roles of pleckstrin homology domain interacting protein	–	[94–96]
Lung cancer	–	–	–	TLN1 mutations is associated with NSCLC metastasis Elevating the concentration of TLN1 coupled with PACSIN2 detection can differentiate lung cancer from other malignancies	a kind of potential biomarker and therapeutic target TLN1 detection in the blood by SRM/SIS may be used as an indicator of lung cancer	[101, 102]
Nasopharyngeal carcinoma (NPC)	CNE-1 CNE-2 SUNE-1 C666-1 HONE1 HNE1 NP69 6-10B 5-8F CNE-2 CNE-1	↑ ↑ ↑ ↑ ↑ ↓ ↑ ↑ ↓ ↓ ↓	MiR-429	MiR-429 inhibits the proliferative, invasive, and migratory activities of NPC cells by downregulating TLN1, but the regulatory relationship is not direct Depletion of talin1 expression significantly inhibits migration and invasion ability of NPC cells	a kind of novel prognostic biomarker High expression of talin1 is significantly related to overall survival(OS) and poorer distant metastasis-free survival (DMFS)	[6, 107]
Oral cancer	SSC4 HSC3 TW206 CAL27 SCC-9	↑	–	Knockdown of talin1 reduced oral squamous cell carcinoma (OSCC) adhesion, migration, invasion and growth The overexpression of TLN1 is related to more aggressive OSCC	A poor prognostic marker	[111, 112]
Breast cancer	MDA-MB-231 BT-549 MCF-7 SK-BR-3	–	–	TNBC tumors typically exhibit significant TLN1 upregulation that is related to worse prognostic outcomes, with TLN1 binding to integrin β1 contributing to greater tumor malignancy and metastatic potential such that silencing TLN1 can suppress TNBC tumor growth, adhesion, and metastatic progression The burden of breast cancer burden can be significantly decreaased by siRNAs targeting TLN1 at all time points The loss of TLN1 function greatly reinforces chemosensitivity in four TNBC cell lines TC67399 is capable of blocking TLN1 binding interactions with integrin β1, thereby repressing TNBC cell metastatic potential	Associated worse prognosis of TNBC	[116–118]
Prostate cancer (PCa)	PC3 PC3-MM2 C4-2B4	↑	MiR-124 and CDK5	Talin1 can promote the migration and metastasis of prostate cancer cell MiR-124 is capable of impairing PCa cell adhesion, invasivity, and migratory activity through its ability to suppress the expression of TLN1 Phosphorylation of talin1 mediated by CDK5 results in β1 integrin activation to promote PCa bone metastasis and increases the ability of anoikis resistance, migration and invasion in PCa TLN1 upregulation was posited to be associated with the malignancy of PCa tumors and their metastasis to the lymph nodes, with a combination of elevated TLN1 levels and a Gleason score > 7 aiding in the prediction of PCa tumor lymph node metastasis	Autoantibodies to talin1 is a biomarker of prostate cancer	[7, 10, 120–122]
Osteosarcoma (OSA)	SAOS-2 U2OS	–	–	The motility of U2OS OSA cells is inhibited, while siRNA of RUNX2 or TLN1 is depleted	–	[127]

The ability of cells to effectively migrate necessitates their precisely coordinated attachment to the ECM [131]. Integrins are the primary receptors responsible for mediating interactions between cells and the ECM, and their activity is carefully regulated by a range of mechanistic processes [132]. FAs are complexes comprised of integrins, actin bundles, and related interacting factors that ultimately support the maturation of robust cell-ECM adhesion interactions [34]. In addition to serving as a key mediator of the activation of integrins [128–130], TLN1 also serves as a core mediator of the recruitment of vinculin and the formation of mature FAs [37, 38]. TLn1 has also been demonstrably linked to the metastasis of many cancers including OSC, CRC, PCa, TNBC, NSCLC, OSCC, NPC, GC, liver cancer, CC, and glioma [6, 10, 11, 72, 76, 85, 89, 94, 101, 112, 116], but there remain many important areas for further research focused on this key adhesion-related proteins. Further efforts focused on elucidating its mechanistic role in the context of tumor metastasis are thus vital.

TLN1 plays a complex role in the tumor microenvironment (TME), affecting both the development of tumors and immune interactions. Previously, we noted that TLN1 impacts tumor migration, invasion, and proliferation via various pathways. It is also linked to various immune cells, indicating its significance as an immune marker in AML. In the TME, TLN1 plays a crucial role in hematologic cancers like AML by influencing cell proliferation, differentiation, and immune interactions. Cui et al. [69] found TLN1 is key in neutrophil-mediated immunity and activation, interacting with molecules like MYH9, PIP5K1C, and ROCK1, potentially affecting immune cell behavior and tumor progression. AML proliferation is inhibited and differentiation is promoted by silencing TLN1 through Talin1/P-AKT/CREB, suggesting that TLN1 could be a therapeutic target [69]. Although research on TLN1 in the tumor microenvironment is limited, existing studies indicate its significant value.

High TLN1 levels have been reported in many cancer types wherein it impacts important malignancy-related processes such as such as invasivity, proliferation, and metastasis. As such, analyzing TLN1 can aid efforts to predict or monitor the prognosis, therapeutic responsivity, and survival of cancer patients. TLN1 has been established as a prognostic biomarker in NPC, OSCC, TNBC, CRC, AML, and OSC, and it is associated with poor prognostic outcomes in OSCC, TNBC, and OSC [6, 69, 71, 92, 112, 116]. The GEPIA database suggests that TLN1 expression levels are closely associated with the overall survival of certain cancer types, including kidney renal clear cell carcinoma, adrenocortical carcinoma, and brain lower-grade glioma (Fig. 5). Efforts to assess TLN1 expression can aid in the early detection and more effective treatment of affected patients, improving their quality of life. TLN1 can also help differentiate among different tumor types when employed as a diagnostic biomarker together with other relevant genes of interest. For example, it is possible to distinguish lung cancer from other forms of cancer based on higher blood TLN1 and PACSIN2 levels [102]. While TLN1 offers prognostic and diagnostic utility, the specificity and accuracy of TLN1-based predictions have not been systematically assessed in detail. In CRC, TLN1 is related to TNM staging, tumor size, liver metastasis, and lymph node metastasis [88, 91]. In OSC, miR-9 overexpression suppressed TLN1 expression to compromise invasivity, migration, and proliferation [72]. CircRNA_400029 and miR-1285-3p can also control TLN1 levels to shape CC cell proliferative, invasive, and migratory activity [76]. Zhang et al. [92] suggested that TLN1 is a valuable biomarker for CRC treatment. As such, TLN1 may drive proliferation and metastatic progression in many cancers such that it is a promising target for therapy. Most TLN1-focused studies to date have explored the functions of this protein and its regulatory roles in particular cancers, but additional analyses of its mechanistic functions in this setting are needed. Understanding the structural, target, and mechanistic characteristics of TLN1 in particular malignancies requires improvement. By clarifying related signaling pathways and interacting targets, it may be possible to identify other targets for treatment and to formulate novel therapeutic strategies. There is also a pressing need for larger cohort studies aimed at validating the relevance and clinical performance of TLN1 as a diagnostic, prognostic, and therapeutic biomarker. In summary, TLN1 studies conducted to date have yielded invaluable insights into the mechanisms that govern tumor progression while having key implications for oncogenic progression. Additional studies will provide further insight into how TLN1 functions in cancer and will help clarify its therapeutic utility.

Fig. 5.

The impact of varying TLN1 expressions on overall survival in certain malignant tumor patients, based on GEPIA data from November 28, 2023. While not statistically significant, the trend indicated that higher TLN1 TPM correlates with better overall survival (OS) in CHOL (cholangio carcinoma), number high = 18, number low = 18 (n(high) = 18, n(low) = 18) A. While not statistically significant, the trend indicated that lower TLN1 TPM correlates with better OS in LAML (acute myeloid leukemia), (n(high) = 53, n(low) = 53) B. In KIRC (kidney renal clear cell carcinoma), patients with high TLN1 TPM have better OS than those with low TLN1 TPM, (n(high) = 258, n(low) = 258), P ≤ 0.05 C. In ACC (adrenocortical carcinoma), patients with low TLN1 TPM have better OS than those with high TLN1 TPM, (n(high) = 38, n(low) = 38), P ≤ 0.05 D. In LGG (brain lower grade glioma), patients with low TPM have better OS than those with high TLN1 TPM, (n(high) = 257, n(low) = 257), P ≤ 0.05 E

Conclusion

To sum up, this review provides a comprehensive overview of the functional roles that TLN1 plays both in healthy cells and in the context of tumor development and progression. TLN1 is, for example, vital for integrin activation and FA formation, and it engages in autoinhibitory activity. It can also serve as an oncogenic driver of tumor metastatic progression, invasivity, and proliferation while also offering utility as a possible tumor-related biomarker. However, research focused on the roles that TLN1 plays remains limited such that additional studies are warranted to expand current knowledge on this topic.

Author contributions

Conceptualization: S.X.L. and A.J.C.; Methodology: J.D.G. and H.S.Z.; Investigation: L.J.Z. and Y.Y.M.; Writing-Original Draft Preparation: S.X.L., A.J.C., J.D.G. and H.S.Z.; Writing-Review and Editing: L.J.Z. and Y.Y.M.. All authors have read and approved the final manuscript.

Funding

This research was financially supported by the following entities: the National Natural Science Foundation (No. 81802576), Wuxi Commission of Health and Family Planning (No. T202102, Z202011, M202330), and Talent plan of Taihu Lake in Wuxi (Double Hundred Medical Youth Professionals Program) from Health Committee of Wuxi (No. BJ2020061, BJ2023051). Additionally, the Clinical trial of Affiliated Hospital of Jiangnan University (No. LCYJ202227, LCYJ202323) and Research topic of Jiangsu Health Commission (Z2022047) also provided funding support for this study.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.