Ran GTPase and Its Importance in Malignant Phenotype

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1		Mohamed El-Tanani	--	2558	2023-04-19 13:07:19	\|
2	format correct	Jessie Wu	+ 9 word(s)	2567	2023-04-20 05:50:15	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijms24043065

Ran is a member of the Ras superfamily of proteins, which primarily regulates nucleocytoplasmic trafficking and mediates mitosis by regulating spindle formation and nuclear envelope (NE) reassembly. Therefore, Ran is an integral cell fate determinant. It has been demonstrated that aberrant Ran expression in cancer is a result of upstream dysregulation of the expression of various factors, such as osteopontin (OPN), and aberrant activation of various signaling pathways, including the extracellular-regulated kinase/mitogen-activated protein kinase (ERK/MEK) and phosphatidylinositol 3-kinase/Protein kinase B (PI3K/Akt) pathways.

Ran GTPase mitosis metastasis osteopontin aneuploidy

1. The Roles of Ran within the Cell

Ran is a member of the Ras superfamily of proteins. Ran exists in two states, Ran GTP and Ran GDP, forming the Ran cycle. The balance between these two states is maintained by the action of the guanine nucleotide exchange factor of regulator of chromosome condensation 1 (RCC1), converting GDP to GTP, and the activation of Ran’s intrinsic GTPase activity through association with Ran guanine activating proteins (Ran GAP) and Ran binding proteins, leading to the hydrolysis of GTP ^[1]^[2]^[3]. Through the action of this cycle, Ran acts as a regulator of normal cellular function, mediating several important processes ^[4].

2. The Overexpression of Ran Alters Cellular Growth and Proliferation and Is Present in Cancer

Upon transfection of fibroblasts with the constitutively active Ran mutant F35A ^[5], it was found that Ran overexpression has a significant effect on cell proliferation. The transfected cells exhibited a greater capacity for proliferation, a lack of contact inhibition, and a higher cell density than the wild-type cells. Additionally, cells were able to develop in an anchorage-free environment. Additionally, animals injected subcutaneously with cells transfected with constitutively active Ran developed tumors, indicating its role in neoplastic transformation ^[6]. The Ran cycle is essential for regular cell activity; therefore, when Ran is expressed abnormally, as it is in certain tumor cells, aberrant cell growth and cell division are stimulated. In contrast to the modest expression reported in normal tissue, tumor cells express a significantly higher quantity of Ran GTP. In addition, Ran is present ubiquitously in aberrant tissue ^[7]^[8]. The overexpression of Ran was elevated at both the mRNA and protein levels in gastric adenocarcinomas. In contrast, normal cells within the tumor tissue did not exhibit higher levels of Ran ^[9]. In mouse tissue, it was discovered that lymphoma cells entering the liver had elevated levels of Ran, whereas surrounding hepatocytes had normal levels. In addition, Ran expression was found to be significantly higher in a variety of human malignancy tissues compared to normal tissue, such as in colon, breast, lung, and renal cell adenocarcinomas ^[7]^[8].

2.1. Ran Overexpression

The overexpression of Ran is associated with increased malignancy and invasiveness. This correlation was determined by comparing the levels of gene expression in non-invasive and invasive cell lines. Ran expression was elevated in invasive cell lines in comparison to non-invasive cell lines. The increase in Ran expression between cell lines corresponded to the difference in osteopontin (OPN) expression ^[10]. This shows that Ran expression is associated with osteopontin expression. By transfecting an OPN expression vector into benign, non-invasive breast Rama 37 cells, the mRNA and protein levels of OPN and RAN were shown to be increased. Transfection with a Ran expression vector enhanced Ran expression but had no effect on OPN levels. Moreover, the transfection of OPN-overexpressing cells using OPN antisense cDNA decreased the levels of both OPN and Ran proteins, whereas small interfering RNA (siRNA)-RAN exclusively reduced Ran protein levels. These results indicated that Ran is an effector downstream of OPN ^[6]^[11]. This showed that the overexpression of osteopontin and the subsequent overexpression of Ran plays a crucial role in neoplastic transformation. In vitro, the overexpression of Ran increases cell adhesion, colony formation rate, and invasive potential ^[12]^[13]. Moreover, the implanting of Ran and OPN-expressing cells into rats resulted in the development of tumors with metastases ^[12]. Cells transfected with siRNA-Ran and cells expressing osteopontin and Ran had significantly different rates of tumor formation compared to untransfected cells. In addition, the silencing of Ran resulted in lower levels of cell invasion in vitro and in vivo compared to cells with a constitutive Ran expression vector ^[11].

2.1.1. Ran Overexpression and Malignancy in Human Cancers

Increased osteopontin expression has been recognized as a critical factor in malignant transformation and cancer. In conjunction with the overexpression of Ran in osteopontin-transformed Rama37 cells, Ran has been identified as an osteopontin effector. Consequently, Ran overexpression is related to enhanced mammary epithelial invasion and metastases ^[11]^[14]^[15]. In addition, Ran overexpression has been seen in a number of different cancer types ^[7]^[8]. Overexpression has also been identified in acinar clear cell carcinoma, in which tumor cells express a considerably higher amount than the normal kidney tissue surrounding them. Immunohistochemistry staining demonstrated that the level of Ran in the nuclei of tumor cells was significantly greater than that of normal cells. The change in expression was similarly correlated to the tumor grade and, subsequently, the worsening of the prognosis, with sarcomatoid features exhibiting the highest levels of Ran expression. The presence of sarcomatoid markers indicates a poorer prognosis. Patients with metastases had higher levels of Ran than those without ^[16]. In general, across all grades of tumors, Ran was expressed at a higher level in metastatic malignancies ^[17]^[18]. Ran expression is also associated with increased cancer risk in epithelial ovarian tumors. This is because Ran and RanBP1 are more frequently overexpressed in invasive tumors than in those with low cancer risk ^[3]^[19]^[20]^[21].

2.1.2. Ran Expression and Survival Time

The link between Ran and the malignant phenotype can be determined by analyzing variations in prognosis in cancer patients ^[22]. A survival curve was generated for patients with breast, lung, melanoma, and renal clear cell carcinoma. Based on the average expression level, these patients were assigned either a high or low expression level. Through this research, increased Ran expression was found to be associated with decreased overall survival. In patients without metastases undergoing nephrectomy or nephron-sparing surgery, higher expression was likewise associated with shorter disease-free survival ^[17]. Ran expression has also been connected to a decreased median survival time in patients with breast cancer ^[23]. Higher Ran expression in the nuclei and cytoplasm of malignant cells within primary tumors was related to a shorter survival time ^[24]. This was also demonstrated to be independent of other parameters, including tumor size, grade, and lymph node involvement. Ran expression in lung cancer resembled these findings; increased Ran expression was associated with a shorter survival time. In tumors with mutations or overexpression of proteins in several signaling pathways, a high level of Ran expression was associated with a decreased survival time. This includes the PIK3CA mutation found in breast cancer patients, which activates the PI3K/Akt/mTORC1 pathway ^[25]^[26]. In lung cancer, increased Ran expression drastically decreased the median survival time of individuals who overexpressed the mesenchymal–epithelial transition factor (c-Met) ^[27]^[28]. Similarly, increased Ran expression significantly decreased survival time in patients’ tumors that expressed OPN. In addition, patients with an elevated amount of Ran-coding mRNA in both breast and lung cancer had a worse prognosis than those with a low expression level. These outcomes were also reported in colorectal cancer patients with PI3K and K-Ras mutations; increased Ran expression was associated with a shorter survival time ^[29]^[30]^[31]. Moreover, Ran is overexpressed in numerous human cancers, including those of the stomach ^[9]^[32], lung ^[29]^[33], head and neck ^[34], pancreas ^[35], ovary ^[36], malignant melanoma ^[37], colorectal ^[38], and kidney ^[17], but not in non-tumor tissue ^[37].

3. Mechanism of Altered Expression—Ran Is a Downstream Effector of the PI3K/Akt and Extracellular-Regulated Kinase/Mitogen-Activated Protein kinase Pathways

Various tumor cell types are dependent on oncogenic pathways for growth, proliferation, and prolonged survival. In cancer, the PI3K/Akt/mTORC1 and Ras/mitogen-activated protein kinase/ extracellular-regulated kinase (MEK/ERK) pathways are both frequently hyperactivated ^[29]^[39]^[40]. The mechanisms that lead to alterations in Ran expression are not well understood. However, Ran has been shown to be an effector of multiple signaling pathways implicated in cancer. Ran is a downstream effector of Akt; hydrogen peroxide, which possesses the ability to induce mitosis in cells, has been shown to induce the phosphorylation of Akt and subsequently increase Ran expression ^[41]. Furthermore, the inhibition of PI3K prevented the induction of mitosis and prevented the phosphorylation of Akt and the subsequent downstream effects on Ran expression, demonstrating that PI3K is involved upstream ^[42]. When breast cancer cells were treated with separate inhibitors for both the PI3K and MEK pathways, silencing of Ran resulted in a greater degree of apoptosis than under normal conditions, suggesting that the abnormal activation of these pathways leads to tumor cell dependence on Ran ^[29]^[43]^[44].

3.1. Aberrant Control of Pathways and Tumor Cell Dependence on Ran

Ran silencing in cells expressing the K-Ras mutant led to a significant increase in apoptosis in comparison to those expressing the wild-type gene. In addition, the inhibition of PI3K or MEK dramatically reduced the apoptosis of these cells ^[29]^[45]^[46]. Higher levels of phosphorylated Akt and c-Met were found in cells transfected with Ran expression vectors ^[11]. c-Met has been demonstrated to activate PI3K, hence influencing the activation of Akt downstream targets ^[47], and has also been shown to depend on the Erk pathway ^[48]. Moreover, c-Met has been linked to lung, breast, and colon cancer, and others ^[49]. Several mechanisms for this effect have been found, including overexpression by gene amplification and the secretion of growth factors and activation via persistent activation of kinases ^[50]. As demonstrated in breast cell carcinoma, the phosphorylation of c-Met is related to the activation of many downstream signaling pathways, resulting in increased tumor cell motility and invasion potential ^[51]^[52]. Ran silencing was performed in two cell lines to study the role of c-Met in tumor cell survival: HCC827 cells, which have high levels of c-Met phosphorylation, and HCC87 GR5 (GR5) cells, which overexpress total and phosphorylated c-Met ^[53]^[54]. Ran silencing resulted in increased levels of apoptosis in GR5 cells, indicating that cells with amplified c-Met are more susceptible to Ran-silencing-induced apoptosis and are consequently more dependent on Ran for survival ^[55]. Ran has a tendency to induce apoptosis to a greater extent in abnormal cells, resulting in the abnormal activation of these pathways ^[43]^[56]. This shows that Ran is a downstream effector of these pathways, and that the hyperactivity of these pathways induces the survival dependence of tumor cells on Ran.

3.2. Signaling Pathways Phosphorylation of Ran Binding Proteins and Control of Ran Expression

In addition to the direct effect of signaling pathways on Ran expression, aberrant signaling pathway regulation was shown to indirectly influence the Ran gradient through phosphorylation and, therefore, the regulation of the activity of Ran binding protein 3 (RanBP3). Phosphorylation occurs through the activity of RSK and Akt, which are downstream from Ras/ERK and PI3K, respectively. RSK has been shown to possess the ability to phosphorylate RanBP3 ^[57]^[58]. Additionally, the knockdown of RSK1 and 2 blocked RanBP3 phosphorylation. Akt can also phosphorylate RanBP3. Similar to RSK, the addition of a PI3K inhibitor prevented the phosphorylation of RanBP3 ^[57]. Results suggest that phosphorylation may increase RanBP3′s binding affinity for Ran; increased interaction between the two was observed upon serum addition. This interaction was also inhibited by the addition of PI3K and MEK/ERK inhibitors. RanBP3 phosphorylation alters the nucleocytoplasmic balance of Ran; this was demonstrated through the knockdown of Ran BP3. In control cells, Ran GTP was distributed primarily within the nucleus, whereas in knockdown cells, a significant amount of Ran GTP was located in the cytoplasm. This is due to the inhibitory effect of phosphorylated RanBP3 on RCC1 and has consequences for cellular function ^[57].

3.3. Altered Ran Expression and Regulation of Cellular Function and Nucleocytoplasmic Transport

The phosphorylation of RanBP3 and subsequent changes in relative Ran concentrations had a profound effect on the efficiency of nucleocytoplasmic transport, as demonstrated through the analysis of the transport of ribosomal protein L12. Knockdown cells expressing the RanBP3 mutant S58A demonstrated reduced transport ability when compared with wild-type RanBP3. Additionally, knockdown cells expressing the mutant displayed reduced cell proliferation relative to the control cells ^[57]. Ran’s role in nucleocytoplasmic transport was identified by silencing it, as this had a profound effect on the distribution of transcription factors. Ran appears to have a significant influence on nucleocytoplasmic transport within cancer cells, altering the relative concentration of certain transcription factors within the nucleus and cytoplasm. This dysregulation appears to be dependent on active PI3K/Akt and MEK/ERK pathways in cancer cells. Ran silencing increased the nuclear localization of p53, p27, and C-jun while decreasing the nuclear localization of β-catenin. In breast cancer cells, Ran silencing decreased -catenin and NFκB nuclear localization while increasing p53 and p27 localization ^[59]. The PI3K inhibitor PI103 and the Akt pathway inhibitor rapamycin partially reversed the altered localization of β-catenin, p53, and p27 in lung cancer cells. The altered localization of β-catenin and p27 in breast cancer cells was reduced by the addition of PD184352, an MEK1 inhibitor, and rapamycin ^[60]. These data suggest that Ran expression can alter nucleocytoplasmic transport, thus influencing transcription factor distribution in cancer cells. This appears to be dependent on the activation of the MEK/EKT and PIK3/AKT pathways ^[29].

3.4. Effect of Ran Expression on Spindle Formation and Tumor Cell Survival

Ran expression appears to operate as a mitotic mediator in tumor cells, a crucial factor in the survival of cancer cells. Due to the loss of Ran-regulated microtubule production, it has been shown that Ran inhibition leads to abnormal mitosis and eventual cell death in breast cancer cells ^[61]. Abnormal mitosis was linked to the flattening of mitotic spindles, the depletion of microtubules, the irregular segregation of chromosomes, and the lack of TPX2 release. The cells died because of the production of hypodiploid DNA. Comparatively, the silencing of Ran in several types of normal cells exhibited no substantial effect on cell-cycle progression or cell viability ^[7]^[8]. It has also been demonstrated that Ran-dependent mitosis is necessary for the survival of K-Ras-activated cancer cells. Using siRNA to silence Ran and TPX2 in these cells resulted in decreased survival relative to cells in which the K-Ras gene was disrupted ^[62]. Ran and TPX2 knockdown led to cell cycle arrest and subsequent cell death ^[45]. It has also been demonstrated that a Ran-Survivin complex pathway is favored by tumor cells. The disruption of the formation of survivin-Ran complexes impeded the delivery of the effector TPX2 to microtubules in tumor cells, resulting in uneven mitotic spindle formation and perturbed chromosomal separation. This had no effect on normal cells, suggesting that tumor cells use this pathway over the traditional Ran pathway to promote their survival ^[7]^[8]. In epithelial ovarian cancer (EOC), the loss of Ran from EOC cells leads to the activation of apoptosis ^[36], which provides more evidence for the dependence of tumor growth and progression on Ran.

Moreover, it has been demonstrated that Ran is a new effector of multiple genes involved in spindle control. One such gene is the tumor suppressor gene RASSF1A. RASSF1A causes phosphorylation of RCC1 in the normal phenotype, resulting in the buildup of RanGTP ^[63]^[64]. This promotes the hyperstability of microtubules. The promoter region of this gene becomes hypermethylated in various forms of cancer, resulting in an increased incidence of tumor growth in mice. The reduction of RASSF1A causes misallocation of RCC1, which causes a buildup of Ran GTP around the mitotic spindle and at spindle poles ^[64]^[65]. This induces improper spindle assembly, resulting in aneuploidy and eventual tumor growth. This suggests that Ran plays a crucial regulatory role inside the cell and that aberrant expression can precipitate cellular abnormalities ^[66].

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