Cellular machinery uses numerous molecular mechanisms to adapt to microenvironment, providing evolutionary success and cell survival. Biological processes associated with stress responses play significant roles in normal development and homeostasis. These biological mechanisms of stress adaptation contribute to formidable cellular resilience. However, these same biological events can also contribute to cellular degeneration over time, invariably culminating in aging and/or disease (Fuchs and Steller, 2015). Among the types of cellular disturbances, we can mention: DNA damage agents, which activate specific repair pathways (Chang et al., 2017; Galluzzi et al., 2018), heat shock or toxin-causing agents, which activate the unfolded protein response (UPR) in the endoplasmic reticulum (ER) and mitochondria (Galluzzi et al., 2018; Hetz and Papa, 2018), hypoxia, respiratory poisons and xenobiotics, which cause mitochondrial stress (Galluzzi et al., 2018; Suomalainen and Battersby, 2018), nutrient deprivation, which activates autophagy (Galluzzi et al., 2017; Galluzzi et al., 2018), and infectious agents, leading to multiples stress responses (Cao, 2016; Galluzzi et al., 2018). To combat these adverse conditions, cells activate fast and transient programs that adjust both RNA and protein synthesis, cytoskeletal and membrane integrity, as well as cell homeostasis (Richter et al., 2010; Vihervaara et al., 2018). In each cell, organelles employ autonomous signaling strategies, which detect and communicate dangerous conditions to both cytosol and nucleus, inducing specific and global transcriptional responses (Walter and Ron, 2011; Vihervaara et al., 2018). This communication is achieved by multiple mechanisms, including (but not limited to) changes in the shape of stressed cells and their connections with the microenvironment, the exposure of specific molecules on its surface, and the active or passive release of bioactive factors, such as ions, small metabolites, intracellular proteins, cytokines, or microvesicles (Galluzzi et al., 2018). Multiple potentially harmful perturbations of the intracellular or extracellular microenvironment can be successfully managed by mammalian cells after activating stress responses that preserve cellular functions and repair macromolecular damage (Galluzzi et al., 2018).

Understanding the molecular mechanism as well as the change in the gene expression profile, in response to cellular stress, had been an important issue for the Oncology (Chen and Cubillos-Ruiz, 2021). In this cellular context, the analysis of the gene expression, in response to stress, has been one of the methodological strategies. Many genes have been studied as biomarkers for various diseases and cancer. NIBAN1 is one of these gene, whose expression is unregulated in many cancer and diseases, such as renal cancer (Majima et al., 2000; Adachi et al., 2004; Hino, 2004; Sun et al., 2007; Feng et al., 2019), lung cancer (Ji et al., 2012; Zhang N. et al., 2019), head and neck carcinoma (Ito et al., 2010), thyroid cancer (Cerutti et al., 2004; Maciel et al., 2005; Cerutti et al., 2006; Matsumoto et al., 2006; Cerutti, 2011; Patel et al., 2011; Carvalheira et al., 2013; Carvalheira et al., 2015; Nozima et al., 2019), gynecologic cancers (Yuki et al., 2015; Evstafieva et al., 2018; Salgado-Albarrán et al., 2019; Wang et al., 2020; Chen et al., 2021), prostate cancer (Shaw et al., 2016; Thomas et al., 2016; Pällmann et al., 2019), brain cancer (Miller et al., 2011; Qaisiya et al., 2017), bladder cancer (Zhu et al., 2018; Jiang et al., 2020) and colorectal cancer (Tan et al., 2021; Wang et al., 2021). The NIBAN1 expression has also been observed in some diseases such as, renal interstitial fibrosis (Liu et al., 2014; Tang et al., 2019; Tang et al., 2021), in asthmatic patients treated with glucocorticoids (Yick et al., 2013; Yick et al., 2014), arterial diseases (Chen et al., 2019), vasomotor dysfunction (Luo et al., 2017; Yim et al., 2020), liver diseases (Kannangai et al., 2005), and pancreatic diseases (Zhang K. et al., 2019). This review analyzes the-state-of-the-art regarding to NIBAN1 gene and its biological role in response to cell stress.

The NIBAN1 gene encodes a protein that belongs to the FAM129 family (family with sequence similarity 129). This protein family is encoded by three genes: NIBAN1, located at 1q25.3 (aliases: C1orf24; FAM129A; NIBAN; GIG39); NIBAN2, located at 9q34.11 (aliases: OC58; MEG-3; C9orf88; FAM129B; MINERVA; bA356B19.6), and NIBAN3, located at 19p13.11 (aliases: BCNP1; FAM129C). These genes share a pleckstrin homology (PH) domain (PH) in their N-terminal region. The PH domain seems to be involved in signaling, cytoskeleton organization, membrane trafficking, and phospholipid processing (Lenoir et al., 2015). Amino acids sequence analysis of the FAM129 family members revealed that they share a common PH domain on their N-terminal region with high sequence similarity of 57% between NIBAN1 and NIBAN2, and 27% between NIBAN2 and NIBAN3 (Old et al., 2009).

These genes have significant cellular functions for many diseases and carcinogenic processes. As mentioned before, the NIBAN1 protein is highly expressed in several diseases and cancer cells, and may play an important role in cell maintenance, such as cell stress (Adachi et al., 2004; Sun et al., 2007; Ji et al., 2012; Qaisiya et al., 2017; Nozima et al., 2019; Pällmann et al., 2019; Yim et al., 2020), autophagy (Qaisiya et al., 2017; Nozima et al., 2019), and others survival biological processes (Table 1). NIBAN2 gene seems to be involved in ERK pathway, at least, in human melanoma cells (Chen et al., 2011). On the other hand, NIBAN3 encodes the membrane protein detected in B lymphocytes from chronic lymphocytic leukemia patients that seems to be involved in regulates B-cell receptor (BCR) signaling and B-cell apoptosis (Boyd et al., 2003).

The NIBAN1 gene was described in 2000 by Majima et al. (2000) in renal carcinoma, both in murine and human cell lines. This gene was called “Niban” (“second” in Japanese), as it is the second gene found by Majima group, after Erc (expressed in renal carcinoma). According to the Gene Nomenclature Committee, from 2019, an official nomenclature for this gene was stablished and would be NIBAN1 (Braschi et al., 2019).

The NIBAN1 messenger RNA (mRNA) identified by Majima et al. (2000) presented expression in normal brain, lung, spleen, and skeletal muscle from Wistar rats. In normal human tissues, strong NIBAN1 expression was found in heart, skeletal muscle, pancreas, white blood cells, and prostate, whereas it presented moderate expression in colon and spleen. They also demonstrated that NIBAN1 expression was dramatically increased in the early stage of renal carcinogenesis and that NIBAN1 had a conserved structure between humans and rats. The absence of expression in normal rat/human kidneys and strong expression in tumor suggests an inverse relationship between NIBAN1 expression and progression of renal carcinogenesis (Majima et al., 2000). Although the expression of NIBAN1 has been described more than 20 years ago, its functions are not elucidated yet.

The structure of NIBAN1 gene is located at reverse strand (antisense) of the 1q25.3 region, and has 184,784 kb, according to the coordinates 184.790.724–184.974.508 (GRCh38.p13, Figure 1). This gene has a predicted promoter region containing 9,797 bp, 16 exons, and presents five transcriptional variants (Genome Browser, GRChHg38.p13). Using gene expression data obtained from the Atlas of Human Proteins database (HPA, version: 20.1), under basal conditions, it is observed that smooth muscle, urinary bladder, and salivary gland have high transcriptional levels of NIBAN1, while protein levels are high in breast, bronchus, endometrium, Fallopian tube, liver, pancreas, and tonsil (Uhlén et al., 2005; Uhlén et al., 2015; Uhlen et al., 2017).

In humans, the NIBAN1 protein (ENSP00000356481.3, Figure 1) has 928 amino acids, and its location seems to be in some cellular compartments, such as cytoplasmic (Adachi et al., 2004; Cerutti et al., 2006; Matsumoto et al., 2006; Ito et al., 2010; Zhang N. et al., 2019), membranous (Uhlén et al., 2005; Uhlén et al., 2015; Uhlen et al., 2017), associated with both ER and plasma membrane, at least in prostate cancer (Pällmann et al., 2019), and nucleus (Adachi et al., 2004; Uhlen et al., 2017). It has been shown that under homeostasis conditions, the NIBAN1 protein has a 130 kDa molecular weight. However, under stress conditions, such as heat shock, oxidative stress, hypertonic stress, and endotoxin (lipopolysaccharide) administration, NIBAN1 could be observed in two sizes, 70 kDa and 130 kDa (Adachi et al., 2004). Note that, NIBAN1 isoform had been predicted, containing around 100 aa (ENSP00000414039.1, GRCh38.p13). However, this isoform did not have yet been described in vivo associated with NIBAN1 expression. Under stressful conditions it is suggested that the NIBAN1 moves from the cytoplasm to the nucleus. It is important to address that NIBAN1 has a dnaJ domain in its polypeptide sequence. This domain is found in members of the heat shock protein family, up-regulated under stress conditions (Adachi et al., 2004). Thus, possibly the presence of 70 kDa NIBAN1 may be a consequence of the cellular stress.

It has been described that NIBAN1 protein can undergo several post-translational modifications, being the phosphorylations marker the most common one (Figure 1) (Sun et al., 2007; Ji et al., 2012; Luo et al., 2017; Yim et al., 2020). Ji et al. (2012) suggested that AKT seems to be responsible for the NIBAN1 phosphorylation. According to predictions from the PhosphoSitePlus database (version: 6.5.9.3), NIBAN1 phosphorylation seems to occur at different serine, tyrosine, and threonine residues. On the other hand, acetylation and ubiquitination can occur in lysine residues (Hornbeck et al., 2015).

As mentioned above, NIBAN1 expression occurs in different types of tumors (Majima et al., 2000; Adachi et al., 2004; Cerutti et al., 2004; Sun et al., 2007; Ji et al., 2012; Shaw et al., 2016; Qaisiya et al., 2017; Evstafieva et al., 2018; Zhu et al., 2018; Feng et al., 2019; Wang et al., 2021). Data from The Cancer Genome Atlas (TCGA) integrated into the Pathology Atlas (The Pathology Atlas, version: 20.1) (Uhlén et al., 2005; Uhlén et al., 2015; Uhlen et al., 2017) have shown increased expression of NIBAN1 in several types of cancer, many has been described in both early carcinogenesis process (Adachi et al., 2004; Matsumoto et al., 2006; Ito et al., 2010) and associated with stress response (Adachi et al., 2004; Sun et al., 2007; Ji et al., 2012; Luo et al., 2017; Qaisiya et al., 2017; Nozima et al., 2019; Pällmann et al., 2019; Yim et al., 2020). Under stress conditions, NIBAN1 seems to play an important role in the regulation of apoptosis, preventing cell death and allowing tumor progression (Sun et al., 2007; Ji et al., 2012; Nozima et al., 2019; Pällmann et al., 2019). However, the molecular mechanisms underlining NIBAN1 expression as well as its biological role in carcinogenesis are not elucidated yet.

As stated earlier, the NIBAN1 was overexpressed in early renal carcinogenesis in human and rats (Majima et al., 2000). The dysregulated expression of NIBAN1 has also been described in head and neck squamous cell carcinomas (HNSCCs), as well as in squamous dysplasia of the mucosa of the head and neck (Ito et al., 2010). In these lesions, the NIBAN1 expression has been observed in mild dysplasia, gradually increasing during carcinogenesis. This data suggests that NIBAN1 overexpression may be an important process in HNSCCs initiating carcinogenesis and maintenance of this tumor progression (Ito et al., 2010). In thyroid cancer, increased NIBAN1 expression has been described in different tumors subtypes: microcarcinomas; papillary carcinomas; follicular carcinomas; metastases, and tumors with oxyphilic cytoplasm, such as Hürthle cell carcinoma, and some oxyphilic cells, originating from Hashimoto’s Thyroiditis (Cerutti et al., 2004; Maciel et al., 2005; Cerutti et al., 2006; Matsumoto et al., 2006; Cerutti, 2011; Patel et al., 2011; Carvalheira et al., 2013; Carvalheira et al., 2015; Nozima et al., 2019). Due to the presence of NIBAN1 in many histological thyroid tumors, it has been suggested that this gene may be overexpressed from the early stage of carcinogenesis and remain expressed during neoplastic progression (Matsumoto et al., 2006). Also, in lung cancer, NIBAN1 overexpression was associated with advanced staging, lymph node metastasis, and poor survival rates (Zhang N. et al., 2019). Corroborating these data, in ovarian cancer, NIBAN1 overexpression was related to poor prognosis, chemoresistance, and metastasis (Salgado-Albarrán et al., 2019).

As aforementioned, NIBAN1 expression has been detected in Hashimoto’s thyroiditis. In this type of lesions, thyrocytes are under both chronic inflammation and stress condition, due to oxidative damage, presenting many modified mitochondria with oxyphilic cytoplasm (Ralli et al., 2020). As a result of the cellular characteristics of these neoplasia, it has been suggested that NIBAN1 may be closely associated with altered mitochondrial functions in pre-neoplastic conditions and in oxyphilic tumors (Matsumoto et al., 2006). In prostate cancer, NIBAN1 expression is regulated by androgen receptor (AR) (Shaw et al., 2016). It had been demonstrated the existence of a strong AR transcription factor binding site at the NIBAN1 locus. These data suggest that NIBAN1 may be regulated by androgens, and its expression may increase in hormone-sensitive tissues (Thomas et al., 2016). CBFβ and RUNX2 are others transcription factors that activate NIBAN1 expression in colon cancer (Wang et al., 2021). On the other hand, in ovarian cancer, it had been observed that the BORIS (Brother of the Regulator of Imprinted Sites) transcription factor downregulates both AR and NIBAN1 expression (Salgado-Albarrán et al., 2019). All these data together suggest that NIBAN1 may be a biomarker or even a therapeutic target (Adachi et al., 2004; Cerutti et al., 2004; Cerutti et al., 2006; Matsumoto et al., 2006; Ito et al., 2010; Carvalheira et al., 2013; Zhang N. et al., 2019).

Considering the cell molecular machinery, we emphasize the importance to expand knowledge about the gene functional status in different types of cellular contexts, including diseases and tumorigenesis. The study of gene functions is essential to understand the molecular mechanisms involved in the cellular microenvironment. In this sense, the comprehension of the NIBAN1 function, in many diseases and cancer progression, is fundamental for the management of cell stability as well as both diseases and cancer treatments.

The increased NIBAN1 expression in early tumorigenesis, highlights the significance of this gene in cellular survival. This high expression seems to be associated with stress response in different biological conditions (Sun et al., 2007; Ji et al., 2012; Nozima et al., 2019; Pällmann et al., 2019). In these stressful environments, NIBAN1 downregulates apoptosis to allow the cell survival (Ji et al., 2012; Carvalheira et al., 2015; Feng et al., 2019; Yim et al., 2020). Furthermore, NIBAN1 plays an ambiguous role in relation to apoptosis and autophagy, and the cellular microenvironment is crucial for its performance in these functions (Qaisiya et al., 2017; Nozima et al., 2019). It had been demonstrated that NIBAN1 may be involved with protein translation processes to alleviate the ER stress (Sun et al., 2007; Pällmann et al., 2019). NIBAN1 expression also seems to be associated with the immune microenvironment (Wang et al., 2020; Zhang et al., 2020; Chen et al., 2021; Tan et al., 2021). It is known that the immune microenvironment of the tumor greatly determines the therapeutic effectiveness of immunological cancer treatments (Tang et al., 2021). The NIBAN1 is part of gene signatures, such as immune infiltration (Tan et al., 2021) and in Treg cells (Zhang et al., 2020). Evidence has demonstrated the importance of tumor infiltration in immune cells, such as tumor-associated macrophages and dendritic cells, T helper and cytotoxic T, in tumor progression, therapeutic responses and prognosis (Liu et al., 2020). The overexpression of NIBAN1 in regulatory T cells also has an important correlation, this cell type mainly migrates to inflammatory sites and suppresses several types of effector lymphocytes (Togashi et al., 2019). In fact, in the cancer context, T reg cells are often detected in inflamed tumors. Cancers exploit different immune escape mechanisms that are sometimes dependent on certain intrinsic tumor factors, such as mutations in the driver genes. Thus, the signals provided by these mutations may allow tumor cells to recruit T reg cells, mainly by changing the local environment of chemokines and the metabolic environment. Therefore, alterations in the driver genes may play crucial roles in promoting not only tumor growth but also in evading anti-tumor immunity. Thus, understanding the genetic context and how it influences NIBAN1 expression and the immune environment will yield important results for the understanding of this gene functions (Togashi et al., 2019). Additionally, some studies describe the association of NIBAN1 with cell proliferation and migration (Carvalheira et al., 2015; Yuki et al., 2015; Feng et al., 2019; Zhang N. et al., 2019). All these data demonstrate the NIBAN1 roles in cell survival, and consequently, its biological functions associated with tumor progression. Furthermore, pos-translational modifications in NIBAN1 protein—especially serine 602 phosphorylation—seem to be crucial for its functional activity in apoptosis regulation (Ji et al., 2012; Yim et al., 2020).

Although NIBAN1 has been described more than 20 years ago, its roles in cancer and other cellular contexts still need to be elucidated. The robust study gathered here demonstrates the importance of NIBAN1 for cell stability and survival. However, there is much to understand about its broad functionality as well as its role in diagnosis (Adachi et al., 2004; Cerutti et al., 2004; Maciel et al., 2005; Cerutti et al., 2006; Matsumoto et al., 2006; Sun et al., 2007; Ito et al., 2010; Cerutti 2011; Patel et al., 2011; Carvalheira et al., 2013) and therapeutic use (Luo et al., 2017; Yim et al., 2020).