The role of CEMIP in cancers and its transcriptional and post-transcriptional regulation

CEMIP is a protein known for inducing cell migration and binding to hyaluronic acid. Functioning as a hyaluronidase, CEMIP primarily facilitates the breakdown of the extracellular matrix component, hyaluronic acid, thereby regulating various signaling pathways. Recent evidence has highlighted the significant role of CEMIP in different cancers, associating it with diverse pathological states. While identified as a biomarker for several diseases, CEMIP’s mechanism in cancer seems distinct. Accumulating data suggests that CEMIP expression is triggered by chemical modifications to itself and other influencing factors. Transcriptionally, chemical alterations to the CEMIP promoter and involvement of transcription factors such as AP-1, HIF, and NF-κB regulate CEMIP levels. Similarly, specific miRNAs have been found to post-transcriptionally regulate CEMIP. This review provides a comprehensive summary of CEMIP’s role in various cancers and explores how both transcriptional and post-transcriptional mechanisms control its expression.


INTRODUCTION
Cell migration-inducing and hyaluronan-binding protein (CEMIP), also known as KIAA1199 or HYBID, is a multifunctional protein involved in cell migration promotion and hyaluronic acid (HA) binding.It was initially identified in 1999 from a cDNA library screen (Kikuno et al., 2002).CEMIP is recognized by several aliases, including colon cancer secretory protein 1 (CCP1), transmembrane protein 2-like (TMEM2L), and hyaluronanbinding protein involved in hyaluronan depolymerization (HYBID).The CEMIP gene is located on human chromosome 15q25.1 and encodes 1361 amino acids.Operating as a pro-vascular and pro-inflammatory factor, CEMIP is widely expressed in various normal human tissues such as the brain, lung, and pancreas (Michishita et al., 2006).The subcellular localization and functions of CEMIP vary depending on the cell type.In colon cancer cells, CEMIP is predominantly found in the cytoplasm (Birkenkamp-Demtroder et al., 2011), nucleus (Birkenkamp-Demtroder et al., 2011), and cell membrane (Sabates-Bellver et al., 2007).Its presence in these locations facilitates proliferation, apoptosis, metastasis, and invasion in vitro and in vivo, suggesting its involvement in tumorigenesis and metastasis.In breast cancer, cytoplasmic CEMIP promotes cell proliferation, migration, and invasion CEMIP protein is composed of several domains: SP, G8, GG, WxxW repeats and PbH1 repeats.Among them, the GB domain has eight glycines, and is expected to contain one α-helix and 10 β-strands.GB domain has been reported to bind with EGFR, PlexinA2, ANXA1 and other factors to trigger different signals.Two GG structural domains, each consisting of 7 β-strands and 2 α-helices.The second GG domain can interact with coatomer protein complex α-subunit (COPA) and glycogen phosphorylase kinase β-subunit (PHKB).The function of WxxW repeats is unknown, but its WxxW sequence is highly conserved.PbH1 repeats consists of four parallel β -repeats sequences.It is known that PbH1 repeats domain can bind to O-GLCNAC transfer (OGT), but its specific function is unknown.
These studies collectively highlight the diverse functions of CEMIP, emphasizing the need for further exploration.Substantial evidence supports CEMIP's potential as a biomarker for various diseases, with most preclinical studies showing an association between abnormal CEMIP expression and disease onset.Moreover, CEMIP is implicated in the pathogenesis of several human cancers, including prostate, breast, and colorectal cancer.This review primarily focuses on delineating CEMIP's role in human cancer and its association with the regulation of CEMIP expression.Additionally, it delves into the analysis of how transcriptional and post-transcriptional control mechanisms of CEMIP influence its expression, consequently leading to specific pathological outcomes.The intended audience for this article comprises cancer researchers and peers within related biomedical disciplines, particularly those dedicated to CEMIP research and the development of new cancer drugs targeting CEMIP.

SURVEY METHODOLOGY
This article presents findings derived from a comprehensive longitudinal query analysis of the MEDLINE database hosted on PubMed and Web of Science.The data collection process involved referencing all pertinent literature using specific keywords or their combinations: ''CEMIP,'' ''CEMIP and transcription factors,'' ''CEMIP and chemical modification,'' ''CEMIP and transcriptional regulation,'' ''CEMIP and miRNAs,'' ''CEMIP and post-transcriptional regulation,'' and ''CEMIP and cancers.''The literature citations aim for a comprehensive and impartial coverage of the topic.

THE ROLE OF CEMIP IN CANCERS
In this section, we aim to consolidate pathophysiological evidence supporting CEMIP's involvement in various cancer processes.

CEMIP and prostate cancer
Prostate cancer stands as a prevalent malignant tumor in adult men.Investigations reveal a significant increase in CEMIP expression within human prostate cancer cells compared to control cells.Mechanistically, CEMIP's involvement in angiogenesis is evident through increased semaphoring 3A (sema3A) and decreased levels of vascular endothelial growth factor A (VEGFA), vascular endothelial cadherin (VE-cadherin), phosphorylated erythropoietin-producing hepatocellular A2 (EphA2), and hyaluronic acid polymers (Luo et al., 2022).
Anoikis, a form of programmed cell death activated upon cell detachment from the extracellular matrix (ECM), undergoes alteration in cancer cell metabolism, potentially enhancing survival and metastasis.In prostate cancer cells, CEMIP overexpression, triggered by AMPK/GSK3 β/β-catenin signaling, may promote migration, invasion, and resistance to anoikis via PDK4-mediated metabolic reprogramming (Zhang et al., 2018).Detached cells may also experience non-apoptotic cell death due to rectifying metabolic deficiencies (Hawk et al., 2018).Escaping anoikis or other non-apoptotic cell death is essential for cancer cells to gain metastatic capabilities.Additionally, CEMIP involvement in ferroptosis-a form of programmed cell death induced by iron-has been observed in prostate cancer cells.Upregulated CEMIP facilitates ferroptosis resistance during ECM detachment by promoting cystine uptake.Silencing CEMIP inhibits ferroptosis and cystine uptake (Liu et al., 2022).

CEMIP and colon cancer
Studies indicate a significant increase in CEMIP expression in colon cancer cells compared to controls, correlating closely with poor prognosis in colorectal cancer (CRC) (Tiwari et al., 2013;Weng et al., 2023;Wu et al., 2021).Tiwari et al. (2013) demonstrates CEMIP as one of the Wnt signal targets, with its upregulation inhibiting cell growth by negatively regulating Wnt signal transduction.However, recent findings by Birkenkamp-Demtroder et al. suggest that shRNA-mediated repression of CEMIP expression attenuates Wnt signaling in parental SW480 cells (Tiwari et al., 2013).Further research is needed to clarify CEMIP's exact role in regulating Wnt signaling.
Apart from its direct regulation of Wnt signaling, CEMIP induction through a betacatenin and FRA-1 dependent pathway in BRAF v600E mutated colorectal cancers has been observed (Duong et al., 2018).CEMIP's interaction with MEK-1 sustains ERK1/2 activation, maintaining c-Myc protein levels and providing metabolic advantages (sustaining amino acid synthesis) in these cells.Silencing CEMIP decreases ERK1/2 signaling and c-Myc protein levels, signifying CEMIP's role in the cross-talk between WNT and MAPK signaling in colorectal cancers.
Furthermore, CEMIP's impact on major histocompatibility complex class I (MHC-I) levels in colorectal cancer cells is noteworthy.CEMIP decreases MHC-I expression at the protein level by promoting MHC-I internalization via clathrin-mediated endocytosis, leading to MHC-I degradation in lysosomes.This downregulation inhibits the cytotoxicity of CD8+ T cells, decreasing their antitumor activities (Zhang et al., 2023).CEMIP's downregulation of MHC-I levels on the cell surface plays a crucial role in immune escape, suggesting CEMIP inhibition as a potential approach in cancer immunotherapy.
Moreover, CEMIP functions as an O-GlcNAc transferase (OGT) adapter protein.Its interaction with OGT and β-catenin increases O-GlcNAcylation of β-catenin, enhancing its translocation into the nucleus.Nuclear β-catenin enhances CEMIP transcription, leading to overexpression of glutaminase 1 and glutamine transporters (SLC1A5 and SLC38A2).SLC1A5 and SLC38A2 facilitate glutamine transport into cells, which has been linked to cancer metastasis.Targeting glutamine metabolism combined with CEMIP modulation significantly reduces CRC metastasis (Hua et al., 2021).
These findings underscore CEMIP's value as a prognostic biomarker and a potential therapeutic target for colorectal cancer.

CEMIP and pancreatic cancer
Pancreatic cancer represents a highly malignant tumor, primarily originating from adenocarcinoma in ductal cells.Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense desmoplastic stroma enriched with hyaluronan (HA).Accumulation of HA in PDAC plays a crucial role in cancer invasion and metastasis.Acting as a hyaluronidase, CEMIP degrades hyaluronic acid in the extracellular matrix, reducing its viscosity and promoting cell movement.Comparative analysis reveals a significant increase in CEMIP mRNA levels in pancreatic ductal adenocarcinoma (PDAC) cells compared to non-tumor cells, correlating with poor survival among PDAC patients (Koga et al., 2017) .
Hypoxia amplifies the migratory ability of PDAC cells by upregulating CEMIP expression.CEMIP catalyzes HA degradation, generating low-molecular-weight HA, fostering a favorable microenvironment for PDAC progression (Oba et al., 2021).In vitro studies indicate that CEMIP contributes to the proliferation and migration of PDAC cells (Kohi et al., 2017).The pro-inflammatory cytokine interleukin-1ßincreases CEMIP transcription, enhancing PDAC cell migration.Given the challenges in earlystage pancreatic cancer diagnosis, carbohydrate antigen (CA) 19-9, a pancreatic cancer biomarker, has limited sensitivity and specificity for general screening (van den Bosch et al., 1996).
CEMIP's overexpression in pancreatic cancer correlates with poor survival and advanced stages.Combining CA19-9 data with CEMIP significantly enhances the accuracy of pancreatic cancer detection by complementing each other, thereby improving diagnosis sensitivity and specificity.This combined approach facilitates early-stage pancreatic cancer detection, crucial for enhancing patient survival and treatment outcomes (Lee et al., 2018).Hence, CA19-9 and CEMIP stand as promising biomarkers whose combined use could enhance early pancreatic cancer detection.However, further research is essential to validate their performance in larger, prospective studies and ascertain their role in screening high-risk populations.

CEMIP and lung cancer
Histopathologically, lung cancer divides into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).Current research demonstrates significantly elevated CEMIP mRNA and protein levels in NSCLC or SCLC cells compared to adjacent normal tissues.High CEMIP expression correlates with poor survival among NSCLC patients (Tang et al., 2019).Manipulating CEMIP levels in NSCLC lines-either knocking it out or overexpressing it-led to respective decreases or increases in the expression of epithelialmesenchymal transition (EMT) marker genes, mediated by PI3K-Akt signaling (Tang et al., 2019).CEMIP promotes SCLC cell migration, proliferation and invasion (Li et al., 2020;Li et al., 2023;Mo et al., 2023).
Moreover, CEMIP's hyaluronidase activity leads to the depolymerization of high molecular weight hyaluronic acid into low molecular weight forms.The accumulation of low molecular weight hyaluronic acid activates its receptor TLR2, recruiting c-Src and activating ERK1/2 signaling, thus promoting F-actin rearrangement and SCLC cell migration and invasion (Li et al., 2023).
Studies also reveal that CEMIP disrupts the interaction between FBXW7, an E3 ubiquitin ligase, and c-Myc in SCLC cells (Mo et al., 2023).This interference reduces the ubiquitination level of c-Myc, leading to its stabilization and increased nuclear accumulation.Through its indirect regulation of c-Myc, CEMIP promotes glutaminedependent proliferation in SCLC cells.

CEMIP and breast cancer
Breast cancer, a frequently diagnosed malignancy in women globally, often presents a challenging prognosis.Current research highlights a significant increase in CEMIP expression in breast cancer tissues compared to normal tissues.Elevated CEMIP levels correlate with decreased overall survival among breast cancer patients (Dong et al., 2021;Jami et al., 2014;Kuscu et al., 2012;Xue et al., 2022).CEMIP promotes the proliferation and migration of breast cancer cells by activating STAT3 signaling (Chen, Li & Zhang, 2021b).
Within the tumor microenvironment (TME), CEMIP potentially plays a carcinogenic role by contributing to extracellular matrix formation, elevating cancer-associated fibroblast (CAF), M2 macrophage, and neutrophil infiltration, while reducing CD8+ T cell infiltration (Dong et al., 2021).Recent studies have also linked CEMIP expression in breast cancer to various immune-related molecules, encompassing both immune inhibitors and stimulators, alongside MHC molecules.
In addition to its direct tumor-promoting role, CEMIP might regulate other tumor proteins to enhance its carcinogenic potential.For instance, binding immunoglobulin protein (BiP), known to drive cancer progression and metastasis, undergoes upregulation in breast cancer.CEMIP activation of the BiP promoter upregulates BiP transcript and protein levels in breast cancer cell lines (Banach et al., 2019).

CEMIP and gastric cancer
Gastric cancer, the second most prevalent malignant tumor with high mortality after lung cancer (Jemal et al., 2011), presents multifactorial causation, with Helicobacter pylori infection being a primary factor.Gastric cancer subtypes are classified based on histology, aiding in subtype identification, prognosis, and treatment response (Lauren, 1965).While CA19-9 and CA72-4 serve as biomarkers for gastric cancer, emerging studies also indicate CEMIP's relevance as a diagnostic marker.
Targeting CEMIP emerges as a promising therapeutic strategy for gastric cancer, considering its role in promoting tumor progression, metastasis, and its involvement in multiple signaling pathways.Natural compounds like curcumin, resveratrol, and quercetin have demonstrated the suppression of CEMIP expression and activity in gastric cancer cells, inhibiting glycolysis, migration, and invasion (Zhao et al., 2022) .Furthermore, angiogenesis-targeted therapies like ramucirumab and apatinib may indirectly modulate CEMIP levels by influencing the tumor microenvironment (Nakayama & Takahari, 2023).
However, further research is crucial to elucidate the specific mechanisms and clinical efficacy of targeting CEMIP in gastric cancer.

CEMIP in various other cancers
CEMIP protein levels significantly escalate in laryngeal squamous cell carcinoma, correlating with adverse clinicopathological parameters (Huang et al., 2020).In hepatocellular carcinoma (HCC), high CEMIP expression promotes tumor growth and correlates with reduced patient survival (Jiang et al., 2018;Xu et al., 2019).In glioblastoma, CEMIP downregulation decreases cell proliferation and migration, while its expression aids macrophage migration (Tsuji et al., 2021).Moreover, CEMIP's overexpression in osteosarcoma cells stimulates growth and metastasis by activating Notch signaling (Cheng et al., 2022).However, in chondrosarcoma, CEMIP expression exhibits anti-tumor effects on tumor growth in vivo (Koike et al., 2020).In cholangiocarcinoma cells, high CEMIP expression enhances growth and metastasis, highlighting its oncogenic role (Zhai et al., 2020) In summary, current evidence emphasizes the pivotal role of CEMIP in human cancer development and progression, warranting further comprehensive exploration of its diverse functions in cancer-related processes.

CEMIP: TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL REGULATION Transcriptional regulation
Transcriptional regulation governs gene expression by overseeing the process of DNA transcription into RNA.This orchestration allows cells to respond adequately to developmental and environmental cues by activating or repressing genes as required.This regulation comprises multiple facets, including control by transcription factors and epigenetic modifications like DNA methylation and histone modifications.Present investigations into CEMIP transcriptional regulation have primarily centered around the control by transcription factors.This overview will encapsulate advancements in understanding how transcription factors regulate CEMIP.Additionally, a brief insight into the epigenetic regulation of CEMIP's transcription will be provided.

AP-1
The transcription factor Activator Protein-1 (AP-1) is a dimeric protein complex consisting of Jun, Fos, or ATF subunits (Karin, Liu & Zandi, 1997).Known for regulating numerous target genes, AP-1 s activity is modulated by various signaling pathways.For instance, the absence of bone morphogenetic protein 6 (BMP6) suppresses AP-1 transcriptional activity (Lu et al., 2023).In different cancers, AP-1 s effects vary depending on context (Mathas et al., 2002;Zhao et al., 2014).Engaging with signaling pathways like JNK, ERK, and Notch, AP-1 participates in diverse biological processes.External stimuli such as growth factors or UV radiation activate AP-1, enabling it to bind to specific target gene promoter or enhancer regions, thereby boosting their transcription (Lee, Mitchell & Tjian, 1987).In breast cancer, AP-1 binds to the CEMIP promoter, activating its transcription, and consequently promoting cancer cell growth (Kuscu et al., 2012).Conversely, hindering AP-1 s transcriptional activity might lower CEMIP expression and exacerbate myocardial fibrosis (Lu et al., 2023).Additionally, the CEMIP promoter harbors a potential binding site for JUN, an AP-1 subunit, indicating its role as a potential CEMIP transcriptional activator (Dong et al., 2021).These studies underscore the significance of AP-1 as a transcriptional regulator of CEMIP.
Activated NF-κB robustly enhances gene transcription.Within the CEMIP promoter, multiple distant NF-κB sites exist, although their specific function remains unclear.Nevertheless, NF-κB elements have the capacity to bolster CEMIP promoter activity (Kuscu et al., 2012).Moreover, the endogenous B cell leukemia-3 (Bcl-3) protein is recruited to the CEMIP NF-κB site and is essential for histone acetylation (Shostak et al., 2014).Consequently, NF-κB transcription factors play a pivotal role in activating CEMIP transcription and modulating its biological functions.
In colon cancer, CEMIP mRNA and protein levels surge under hypoxic conditions compared to normoxic conditions.Bioinformatics analyses have unveiled potential HREs in the CEMIP sense strand from positions 125 to 120 bp.Although the depletion of HREs did not entirely suppress CEMIP promoter activity, presumably due to other cis-elements, HIF can directly prompt CEMIP transcription, partially mediated through HIF-2 α (Evensen et al., 2015).Conversely, a separate study did not observe direct HIF-1 α induction of CEMIP; however, it noted a strong correlation between CEMIP expression and HIF-1 α levels in hypoxic hepatocellular carcinoma (Wenger, Stiehl & Camenisch, 2005).These findings collectively underscore the significant role of HIF in governing CEMIP transcriptional regulation under hypoxic conditions

Sp1
Sp1, the pioneering member of the Sp family of transcription factors encompassing Sp2, Sp3, and Sp4, is recognized for its C2H2-type zinc finger structures (Black, Black & Azizkhan-Clifford, 2001;Bouwman & Philipsen, 2002;Kaczynski, Cook & Urrutia, 2003).Sp1 and Sp3 share highly homologous DNA binding domains, with Sp1 displaying three zinc fingers, each imparting distinct binding preferences, while the first finger confers high sequence specificity (Kriwacki et al., 1992;Thiesen & Schröder, 1991).Initially identified as a promoter-specific binding factor essential for the transcription of the SV40 major immediate early (Dynan & Tjian, 1983a;Dynan & Tjian, 1983b).Sp1 and the long isoform of Sp3 contain two transactivation subdomains, A and B, where the D domain of the Sp1 C-terminus is crucial for synergistic activation.Known for its regulatory roles in metabolism, proliferation, apoptosis, and development, Sp1 expression is often heightened in cancer cells, correlating with poorer prognoses in cancers like colorectal, gastric, and lung (Chuang et al., 2009;Davie et al., 2008;Kong et al., 2010).
These Sp factors typically prefer binding to GC box motifs.By binding to GC-rich sites within target gene promoters, Sp1 can activate their transcriptional activity (Hagen et al., 1995;Kingsley & Winoto, 1992;Thiesen & Bach, 1990).Despite the presence of a GC box at positions 248/243 within the CEMIP promoter, a study revealed that removing this specific GC box did not affect CEMIP transcription, creating an apparent contradiction (Kuscu et al., 2012).Therefore, the exact role of Sp1 in inducing CEMIP transcription warrants further investigation.
β-catenin β-catenin, a highly conserved and multifunctional protein, possesses a central region featuring 12 imperfect Armadillo repeats flanked by distinctive N-terminal and C-terminal domains (Valenta, Hausmann & Basler, 2012).Functionally, β-catenin serves as both a structural component within cadherin-based cell junctions and a pivotal nuclear effector of canonical Wnt signaling, controlling cell proliferation.As part of the Wnt pathway, nuclear β-catenin activates the transcription of target genes like c-myc and cyclin D1 (Reiss et al., 2005).
CEMIP has been identified as a target gene of ATF4-containing heterodimers.Through chromatin immunoprecipitation analysis, several potential ATF4 binding sites have been revealed within the CEMIP promoter.Subsequent experiments have conclusively demonstrated that ATF4 induces CEMIP transcription by augmenting CEMIP promoter activity and expression (Yu et al., 2022)

EPIGENETIC MODIFICATION-METHYLATION
DNA methylation stands as a crucial epigenetic mechanism, where DNA methyltransferases transfer methyl groups from S-adenosylmethionine to the C5 position of cytosine, forming 5-methylcytosine (Robertson & Jones, 2000).This mechanism regulates gene expression at the transcriptional level.Typically, CpG islands within gene promoters and exons remain unmethylated under normal conditions.However, in cancer cells, genome-wide hypomethylation is evident, while specific CpG islands undergo hypermethylation.While DNA methylation is generally perceived to inhibit transcription, recent evidence suggests that DNA demethylation can upregulate cancer-related genes.
In a study involving breast cancer cell lines MCF-7 and MDA-MB-231 treated with demethylation agents, distinct responses in CEMIP expression were observed.Notably, CEMIP expression significantly increased in MCF-7 cells, whereas no significant change was noted in MDA-MB-231 cells.Pyrosequencing analysis of breast cancer specimens demonstrated lower levels of average methylation in neighboring CpG sites compared to normal controls, confirming the association between hypomethylation and increased CEMIP expression in breast cancer (Kuscu et al., 2012).Additionally, studies suggest that TP53 mutation might lead to hypomethylation of the CEMIP promoter.TP53, commonly known as a tumor suppressor gene, when mutated, can impair DNMT1 function, a DNA methyltransferase that maintains DNA methylation patterns.Consequently, the CEMIP promoter might lose its methyl groups and become more active (Hsieh et al., 2020).
Moreover, H3K27me3 modification deactivates gene transcription by condensing chromatin.The loss of H3K27me3 specifically characterizes aggressive subtypes of breast cancer and can serve as a valuable diagnostic marker.Epigenetic chemical screening has identified inhibition of histone H3K27me3 demethylation as a therapeutic strategy for triple-negative breast cancer (TNBC).Studies using functional analyses and RNA-seq/ChIP-seq data revealed that inactivating the protein CEMIP by increasing H3K27me3 resulted in reduced tumor cell growth and migration (Hsieh et al., 2020).Hence, methylation presents a multifaceted regulatory role in CEMIP transcription.

POST-TRANSCRIPTIONAL REGULATION
Gene expression undergoes multiple levels of control, including post-transcriptional regulation following the initial transcription phase.Several mechanisms operate at this stage to govern gene expression.One significant process involves alternative splicing of pre-mRNA transcripts, enabling the generation of diverse protein isoforms from a single gene.RNA stability serves as another critical checkpoint-unstable mRNAs degrade swiftly, while stable ones persist longer for translation.RNA stability is modulated by RNA binding proteins and microRNAs, which identify specific sequences or structures within transcripts.MicroRNAs, in particular, bind to complementary regions in target transcripts, silencing gene expression by impeding translation or promoting mRNA decay.Additionally, RNA editing can modify the nucleotide sequence of RNA transcripts, often by converting adenosine to inosine.This process can alter protein-coding sequences or influence mRNA stability.
Regarding post-transcriptional regulation specific to CEMIP, current research predominantly centers on its regulation by microRNAs.The advancements in this field will be summarized to provide an overview of the progress in understanding how microRNAs regulate CEMIP.
Meanwhile, miR-140-3p emerges as a potential biomarker for effective anti-tumor therapy.In cutaneous melanoma (CM), diminished miR-140-3p levels correlate with poorer CM survival rates, whereas overexpression of miR-140-3p impedes cell movement (He et al., 2020).Similarly, in gastric cancer, it suppresses the migration and invasion of gastric cancer cells by binding to SNHG12 and suppressing its expression (Wang et al., 2021).
In colorectal cancer (CRC), a negative correlation exists between miR-140-3p and CEMIP expression.Elevated CEMIP expression fosters the growth, colony formation, and invasion of CRC cells (Yang et al., 2020).Co-transfection experiments involving CEMIP and miR-140-3p in cancer cells demonstrated that miR-140-3p expression inhibits cancer cell growth, and the introduction of CEMIP reverses this inhibition (Yang et al., 2020).Studies indicate that miR-140-3p participates in CRC processes by binding to the CEMIP 3 UTR region and curbing its expression (Yang et al., 2020).

miR-148-3p
miR-148a-3p is a part of the miR-148a family, plays crucial roles in regulating inflammation, immunity, and cancer progression.In laryngeal squamous cell carcinoma (LSCC), it targets DNA methyltransferase 1 (DNMT1), thereby influencing RUNX3 expression through DNMT1-mediated DNA methylation, effectively suppressing cell migration (Jili et al., 2016).Moreover, in gastric cancer, the expression of CEMIP shows an inverse relationship with miR-148a-3p levels.Reduced miR-148a-3p results in heightened CEMIP expression, promoting cell viability while impeding apoptosis.Investigations have confirmed CEMIP as a direct target of miR-148a-3p.The action of miR-148a-3p in regulating CEMIP portrays its role as a tumor suppressor in gastric cancer (Song et al., 2021).The downregulation of miR-148a-3p consequently leads to the upregulation of CEMIP, potentially advancing gastric cancer.Thus, the miR-148a-3p/CEMIP axis represents a promising therapeutic target for intervention in gastric cancer progression.

miR-188-5p
It is derived from non-coding RNA transcribed by the B cell integration cluster gene situated on chromosome 21, closely linked to various human tumors (Wang et al., 2019b).The miR-188 family includes two members: miR-188-3p and miR-188-5p.Studies have revealed abnormal expression of miR-188-5p in various pathological processes in vivo.Notably, miR-188-5p exhibits high expression levels in gastric cancer and liver cancer (Tian et al., 2019).In the context of multiple myeloma, miR-188-5p acts as a tumor suppressor by significantly curbing tumor cell proliferation and fostering apoptosis (Liu et al., 2021a).
In synovial fibroblasts' gene expression profile analysis, miR-188-5p exhibited significant regulatory influence on the hyaluronic acid binding protein CEMIP.Further exploration indicated the presence of a binding site for miR-188-5p in the CEMIP UTR sequence, implying direct regulation of this gene by miR-188-5p (Ruedel et al., 2015).This interaction slows down disease progression in which CEMIP plays a role to a certain extent.

miR-216a
MicroRNA-216a (miR-216a) is closely associated with cancer and has been consistently found to be down-regulated in various cancers including breast cancer (Cui et al., 2019), renal cell cancer (Wang et al., 2018), colorectal cancer (Zhang et al., 2017a), lung cancer (Zhen et al., 2018), among others.Its tumor-suppressive role primarily involves the regulation of multiple signal pathways and transcription factors.For instance, in pancreatic tumors, miR-216a significantly curbs cell proliferation by targeting JAK2 and triggers programmed cell death in pancreatic tumor cells (Hou et al., 2015).
In the context of colorectal cancer, miR-216a has been implicated in the posttranscriptional regulation of CEMIP, influencing cancer development.The upregulation of CEMIP in colorectal cancer tissues promotes tumor invasion and correlates with a shorter survival period (Zhang et al., 2017a).Decreasing CEMIP expression in tumor cells leads to increased expression of epithelial markers (E-cadherin and cytokeratin 8, 18, 19) and decreased expression of mesenchymal markers (vimentin and Twist-1) (Zhang et al., 2017a).Conversely, CEMIP overexpression decreases cytokeratin expression and increases Twist-1 expression.These findings highlight CEMIP's role in promoting the epithelial-mesenchymal transition of colorectal cancer cells (Zhang et al., 2017a).As one of the direct functional targets of miR-216a, down-regulating CEMIP expression inhibits the migration and invasion of colorectal cancer cells in vitro and reduces the risk of metastasis in vivo.
In the context of preeclampsia (PE), there's an abnormal increase in the mRNA level of miR-296-3p.Studies have identified a binding site for miR-296-3p on the CEMIP UTR.Interestingly, in cancer cells, CEMIP can counteract the down-regulation of β-catenin induced by miR-296-3p overexpression, shedding light on a potential mechanism whereby miR-296-3p might promote the PE process through its targeting of CEMIP (Li et al., 2021b).
In colorectal cancer, a significant association exists between miR-600 and KIAA1199 (CEMIP).Notably, miR-600 displays downregulation in colorectal cancer tissues compared to normal tissues, while KIAA1199 mRNA exhibits significant upregulation.Lucidly demonstrated by luciferase reporter assays, miR-600 directly binds to the KIAA1199 3 UTR, solidifying KIAA1199 as a direct target of miR-600 (Sun et al., 2018).
In prostate cancer, miR-4656 is typically downregulated while CEMIP is upregulated.Experimental overexpression of miR-4656 diminishes CEMIP mRNA levels and impedes cancer cell growth.Confirmatory studies established a binding site for miR-4656 within the CEMIP 3 UTR, affirming CEMIP as a direct target of miR-4656.Consequently, the downregulation of miR-4656 can result in upregulated CEMIP expression, fostering the progression of prostate cancer (Hu & Lu, 2020).In summary, miR-4656 demonstrates both tumor-suppressive and oncogenic roles across various cancer contexts, partly through its modulation of oncoproteins like CEMIP.

miR-4677-3p
MiR-4677-3p, a recently identified microRNA, demonstrates varying expressions in different cancer types.In lung cancer, it's upregulated by circ_0001421, which acts as a tumor promoter.Interestingly, overexpressing miR-4677-3p inhibits proliferation and migration of lung cancer cells (Zhang et al., 2020).Conversely, in gastric cancer, miR-4677-3p is downregulated.Its restoration suppresses cell movement by directly binding to the UTR site of CEMIP, consequently inhibiting CEMIP expression.This inhibition leads to decreased proliferation, migration, and invasion of gastric cancer cells (Mi et al., 2021).

CONCLUSIONS
CEMIP (cell migration inducing hyaluronan binding protein) emerges as a pivotal oncoprotein governing cancer advancement through diverse pathways.It orchestrates cell migration, invasion, and signaling cascades by influencing cytoskeletal dynamics, matrix degradation, and crucial signaling pathways like ERK/MAPK.Moreover, its interaction with hyaluronan drives cell motility and adhesion while inducing epithelial-mesenchymal transition, a pivotal step in metastasis.Elevated CEMIP expression correlates with poor prognosis across various cancers.While CEMIP holds promise as a potential target for early cancer diagnosis and therapy, it intersects with immune checkpoint blockade (ICB) therapy, mediating tumor immune escape.Targeting CEMIP may amplify the efficacy of ICB by boosting tumor immunogenicity and augmenting T cell activation and infiltration.
Studies employing CEMIP knockout mice elucidate its role in regulating inflammatory responses, wound healing, and infection.However, further optimization of these models is essential for more effective preclinical research.Efforts in drug development targeting CEMIP have shown promise, revealing its role in drug resistance and its potential as a biomarker for gastric cancer detection, prognostication, and treatment response.
CEMIP's expression is tightly controlled transcriptionally by a cadre of factors like AP-1, NF-κB, HIFs, and β-catenin, in concert with epigenetic modifications such as DNA methylation and histone marks.Furthermore, microRNAs wield post-transcriptional regulation over CEMIP expression, highlighting the intricate control mechanisms underpinning its oncogenic role across various cancers.
The intricate regulatory network that governs CEMIP highlights its pivotal role within diverse cellular pathways involved in cancer.This is visually represented in Fig. 2, while Table 1 provides a summary of its involvement in cancers, detailing both its transcriptional regulation and functional roles.
While recent studies have made headway in understanding CEMIP regulation, several critical questions beckon further exploration.Delving deeper into how signaling pathways like NF-κB, Wnt/β-catenin, and HIF-1 precisely modulate CEMIP expression, particularly in in vivo disease models, remains paramount.Expanding investigations across various cancer types might unveil distinct tissue-specific regulators governing CEMIP
transcriptional control.Extensive mapping of the CEMIP promoter and enhancers could unveil novel regulatory elements and binding sites for transcription factors, augmenting our understanding.Epigenomic analyses represent an avenue to discover new methylation patterns or histone modifications influencing CEMIP expression, fostering a more comprehensive understanding of its regulation.Exploring the intricate interplay between transcription factors and epigenetic alterations is crucial.Further exploration is warranted to identify additional microRNAs or RNA binding proteins that target CEMIP, especially for their role in cancer pathogenesis and metastasis.Investigating mRNA stability, alternative splicing, or translational control mechanisms could shed light on post-transcriptional regulation.In essence, a nuanced comprehension of the multilayered transcriptional circuitry and post-transcriptional regulatory networks governing CEMIP expression holds promise in unveiling novel strategies to target this oncoprotein effectively in cancer therapeutics.
Presently, contradictory or inconclusive findings regarding CEMIP in cancers stem from its dual roles.Some studies suggest its association with tumor progression and aggressiveness, while others indicate its potential as a suppressor of cancer development.These discrepancies might stem from variations in experimental models, sample sizes, or contextual differences among different cancer types.Additionally, the diverse molecular functions of CEMIP across various cellular pathways could contribute to these conflicting observations, highlighting the need for further comprehensive investigations to elucidate its precise role in different cancer contexts.
• Yuanyuan Chen analyzed the data, prepared figures and/or tables, and approved the final draft.
• Shuaishuai Cui analyzed the data, prepared figures and/or tables, and approved the final draft.
• Chunmei Zhang analyzed the data, prepared figures and/or tables, and approved the final draft.
• Dahu Chen conceived and designed the experiments, analyzed the data, prepared figures and/or tables, authored or reviewed drafts of the article, and approved the final draft.

Figure 1
Figure 1 Schematic diagram of secondary structure of CEMIP.CEMIP protein is composed of several domains: SP, G8, GG, WxxW repeats and PbH1 repeats.Among them, the GB domain has eight glycines, and is expected to contain one α-helix and 10 β-strands.GB domain has been reported to bind with EGFR, PlexinA2, ANXA1 and other factors to trigger different signals.Two GG structural domains, each consisting of 7 β-strands and 2 α-helices.The second GG domain can interact with coatomer protein complex α-subunit (COPA) and glycogen phosphorylase kinase β-subunit (PHKB).The function of WxxW repeats is unknown, but its WxxW sequence is highly conserved.PbH1 repeats consists of four parallel β -repeats sequences.It is known that PbH1 repeats domain can bind to O-GLCNAC transfer (OGT), but its specific function is unknown.Full-size DOI: 10.7717/peerj.16930/fig-1 While investigating the tumor biological functions of CEMIP, attention has shifted toward understanding the regulation of CEMIP expression itself.Currently, research on CEMIP's transcriptional and post-transcriptional regulation remains limited.Various factors and chemical modifications of the CEMIP gene contribute to both transcriptional and post-transcriptional regulation.Existing studies indicate that CEMIP transcription can be induced by different transcription factors and microRNAs.

Figure 2
Figure 2 Schematic diagram of CEMIP transcriptional and post-transcriptional regulation and its consequences for cancer development.Transcription factors can enhance the transcription of CEMIP.This leads to promoting cancer development.CEMIP is also regulated by histone methylation.H3K4me3 in the CEMIP promoter region enhances gene transcription activity.On the other hand, H3K27me3 inhibits this process.miRNAs play an important role in CEMIP post-transcriptional regulation, which frequently leads to decreasing CEMIP and consequently inhibiting cancer development.Full-size DOI: 10.7717/peerj.16930/fig-2