KIAA1199: A Novel Regulator of Chemoresistance in Human Cancer Cells

Abstract

KIAA1199 (also known as CEMIP or HYBID), an archived gene listed in the Human Unidentified Gene-Encoded (HUGE) database, has been implicated in tumor progression and metastasis in a wide range of cancers, including breast, cervical, cholangiocarcinoma, pancreatic, colorectal, gastric, hepatocellular, lung, ovarian, prostate, papillary thyroid, and brain cancers. Overexpression of KIAA1199 is significantly correlated with poor prognosis and metastasis and has been clinically associated with chemoresistance. In addition, KIAA1199 may serve as a novel biomarker for cancer diagnosis and prognosis, particularly due to its role in maintaining cancer stem cell properties. However, the molecular mechanisms by which KIAA1199 regulates chemoresistance, prognosis, and cancer stem cell development remain incompletely understood. Therefore, this review aims to summarize the clinical relevance of KIAA1199 as a novel regulator involved in chemoresistance, cancer prognosis, and cancer stem cell biology.

Keywords

KIAA1199 chemoresistance prognosis cancer drug resistance cancer stem cells

Introduction

KIAA1199 (CEMIP, HYBID), a 150 Kda protein encoded by a gene located on chromosome 15q25.1, is an archived gene listed in the Human Unidentified Gene-Encoded (HUGE) protein database.¹ KIAA1199 was initially described in association with nonsyndromic hearing loss,² as well as with cancer initiation and progression,³ osteoarthritis and rheumatoid arthritis,⁴ atherosclerosis,⁵ and idiopathic pulmonary fibrosis.⁶ To date, the HUGE database includes more than 2400 entries, conventionally designated with the prefix “KIAA” followed by a four-digit number, beginning with KIAA0001.⁷ KIAA1199 was first investigated as a protein of unknown function in 1999,¹ and later identified as an inner ear–specific protein in 2003.² It localizes to the cytoplasm,⁸ particularly around the perinuclear region in the endoplasmic reticulum.⁹ Importantly, KIAA1199 detected in cell culture media is a secreted protein rather than a transmembrane protein.³

The KIAA1199 protein consists of 136 amino acids and includes 3 domains and an N-terminal secretion signal sequence. These domains comprise 2 GG domains and 1 G8 domain. The GG domain, approximately 100 amino acids in length and composed of 7 β-strands and 2 α-helices, is involved in hyaluronic acid binding and/or degradation. This is supported by evidence showing that a single mutation in the first GG domain impairs hyaluronidase activity.^2,4 The G8 domain contains 8 conserved glycine residues and 5 consecutive β-strand pairs. While most G8-containing proteins are predicted to be intra- or transmembrane proteins, the G8 domain of KIAA1199 may contribute to its localization.⁸ The N-terminal signal sequence, consisting of 30 amino acids, is responsible for directing the protein into the secretory pathway. Therefore, both the GG and G8 domains are essential to unravel the functional role of KIAA1199.

Gene expression of KIAA1199 is regulated by both genetic and epigenetic mechanisms. Its promoter region contains binding sites for 2 key transcription factors, NF-_KB and AP-1, and its basal promoter activity is influenced by the DNA methylation status of a CpG island within the first intron.¹⁰ In addition, H3K4 trimethylation (H3K4me3), an active transcription marker, enhances KIAA1199 expression,¹¹ whereas H3K27 trimethylation (H3K27me3), a repressive mark, leads to its silencing.¹² Furthermore, H3K4me3 and H3K27me3 modifications occur at both promoter and enhancer regions but with distinct functional roles. H3K4me3 is primarily associated with active promoters and enhancers while H3K27me3 is often found at repressed promoters and enhancer.^13-15 Several microRNAs such including miR-600, miR-216a, miR-29c-3p, miR-140-5p, miR-4656, miR-486-5p,… have been known to significantly regulate KIAA1199 expression.^3,16-20 Moreover, pro-inflammatory cytokines such as interleukin-1β also induce KIAA1199 transcription.²¹

Overexpression of KIAA1199 has been observed in multiple cancers, including breast,¹⁰ non-small cell lung,^22,23 colorectal,^24,25 gastric,^26,27 hepatocellular,^28,29 prostate,³⁰ papillary thyroid,¹⁷ pancreatic,³¹ ovarian,³² and cholangiocarcinoma.³³ Clinically, it might be involved in chemoresistance in various cancers, such as colorectal,^34-36 hepatocellular,³⁷ non-small cell lung,³⁸ and gastric cancer.³⁹ Furthermore, KIAA1199 is a significant indicator of poor prognosis in breast,^40,41 cervical,⁴² cholangiocarcinoma,³³ pancreatic,³¹ colorectal,^16,43,44 gastric,^26,45 hepatocellular,^28,29 lung,^22,23 ovarian,^32,46,47 prostate,^30,48,49 papillary thyroid,^17,50 and brain cancers.⁵¹ Notably, KIAA1199 is also considered a potential regulator of cancer stem cell progression in colorectal cancer.¹⁶ In this review, we summarize the critical relevance of KIAA1199 as a novel regulator in cancer progression, chemoresistance, prognosis, and cancer stem cell development.

KIAA1199 and Progression of Cancer

Cancer proliferation, 1 of the 5 main steps of metastasis, is a fundamental process in which a single transformed cell undergoes rapid division, acquires genetic heterogeneity, and prepares for dissemination.⁵² During this progression, KIAA1199 plays 3 critical roles: (i) modulating cell signaling transduction, (ii) regulating the cell cycle, and (iii) driving metabolic reprogramming, all of which contribute to cancer cell growth and survival. In terms of signaling, KIAA1199 activates key pathways such as EGFR, MEK/ERK, PI3K/AKT, Wnt/β-catenin, and STAT3. In regulating the cell cycle, KIAA1199 either facilitates progression or induces arrest, depending on context. For metabolism, KIAA1199 promotes glycolysis, glutamine metabolism, and amino acid biosynthesis, thus supporting the energy and biosynthetic demands of rapidly proliferating cells.⁵³

KIAA1199 Drives Cancer Cell Proliferation by Modulating Key Cell Signaling Transduction

KIAA1199 enhances cancer cell proliferation by modulating critical cell signaling transductions including EGFR, MEK/ERK, PI3K/AKT, Wnt/β-catenin, and STAT3:

EGFR pathway: KIAA1199 protects cells from Semaphorin 3A-mediated apoptosis by binding to its receptor Plexin A2 and stimulating EGFR signaling, sustaining proliferation and survival in cervical cancer.⁴²

MEK/ERK pathway: In BRAF^V600E-mutated colorectal cancer, KIAA1199 binds MEK1/2, enhancing their phosphorylation along with ERK1/2 and RSK1, thereby promoting proliferation and survival.³⁴

PI3K/AKT pathway: Knockdown of KIAA1199 reduces phosphorylated and total levels of PI3K, AKT, P70S6K, and BCL-2, thus inhibiting growth and promoting apoptosis in ovarian cancer.^32,46

Wnt/β-catenin pathway: Silencing KIAA1199 downregulates β-catenin, c-myc, cyclin D1 and MMPs in gastric^24,27 and colorectal cancers.⁵⁴ Elevated nuclear KIAA1199 correlates with increased nuclear β-catenin.⁵⁴

STAT3 pathway: KIAA1199 induces the ER chaperone GRP78, which activates STAT3 signaling, promoting proliferation and migration in breast cancer.^55,56

KIAA1199 Drives Cancer Cell Proliferation by Regulating Cell Cycle

Knockdown of KIAA1199 induces G0/G1-phase arrest and downregulates cyclin D1 in hepatocellular carcinoma.²⁸ In ovarian cancer, KIAA1199 knockdown causes S-phase arrest, with decreased expression of cyclin A and CDK2.³²

KIAA1199 Drives Cancer Cell Proliferation by Metabolic Reprogramming

KIAA1199 enhances cancer cell proliferation via metabolic reprogramming by promoting glycolysis, glutamine metabolism, and amino acid biosynthesis:

Glycolysis: KIAA1199 activates AMPK, which inhibits GSK3β, stabilizes β-catenin, and upregulates PDK4-mediated glycolysis. Inhibition of PDK4 reduces VEGF, suggesting therapeutic potential in prostate cancer.⁴⁸

Glutamine metabolism: KIAA1199 functions as an O-GlcNAcylation adapter protein then KIAA1199 alters glutamine metabolism by enhancing O-GlcNAcylation of β-catenin which translocate to the nucleus to promote the overexpression of KIAA1199, glutaminase 1 and glutamine transporters (SLC1A5 and SLC38A2). Therefore, co-targeting KIAA1199 and glutamine metabolism suppresses proliferation and metastasis in colorectal cancer.⁵⁷ Moreover, in small cell lung cancer, KIAA1199 stabilizes nuclear c-Myc by preventing its degradation through FBXW7 and stabilized C-Myc enhances the expression of the SLC1A5 driving glutamine-dependent tumor growth.⁵⁸ Therefore, KIAA1199 promotes glutamine-dependent growth via FBXW7/c-Myc regulation in small cell lung cancer.⁵⁸

Amino acid biosynthesis: Through ERK activation, KIAA1199 upregulates Myc, enhancing biosynthesis of amino acids, fatty acids, and proteins. These processes support cancer cell proliferation and activate the mTOR pathway.³⁴

KIAA1199 and Chemoresistance

Overcoming intrinsic and acquired chemoresistance remains a major challenge in the treatment of cancer patients, often leading to recurrence, dissemination, and mortality.⁵⁹ The molecular mechanisms underlying chemoresistance include transporter pumps, oncogene activation, tumor suppressor gene inactivation, mitochondrial alterations, DNA repair mechanisms, autophagy, epithelial-mesenchymal transition (EMT), cancer stemness, and exosomes.^59-61 KIAA1199 has been shown to play a clinical role in regulating chemoresistance in various cancers, including colorectal,^34-36 hepatocellular,³⁷ non-small cell lung,³⁸ and gastric cancer.³⁹ Furthermore, KIAA1199 is involved in the regulation of multiple cell signaling transductions as Wnt/β-catenin,^24,27,54 EGFR,⁴² MEK/ERK,³⁴ PI3K/AKT,^32,46 and STAT3.^55,56 Therefore, KIAA1199 represents a novel target for controlling chemoresistance in cancer.

The RAF/MEK/ERK pathway is crucial in tumor progression.^59-62 Several clinical trials have investigated the effects of allosteric MEK1/2 inhibitors, such as selumetinib, in combination with traditional chemotherapeutics. These include a phase II trial combining FOLFOX and erlotinib as first-line therapy for metastatic colorectal cancer,^60-63 and a phase II trial of selumetinib plus irinotecan as second-line therapy for KRAS-mutated colorectal cancer.^61-64 Notably, selumetinib also overcomes ITGA2-induced 5-fluorouracil (5-FU) resistance in colorectal cancer.^62-65 Importantly, KIAA1199 has been found in endosomes and binds MEK1 to sustain ERK1/2 activation in selumetinib-resistant BRAF^V600E-mutated colorectal cancer.³⁴ Additionally, KIAA1199-dependent pathway maintained c-Myc through ERK1/2 and provided metabolic advantage in resistant cells; and KIAA1199 silencing circumvented resistance to MEK1 inhibition, party, through a decrease of both ERK1/2 signaling and c-Myc.³⁴

Oxaliplatin is a key chemotherapeutic agent for colorectal cancer, functioning by inducing cancer cell apoptosis through the formation of platinum-DNA adducts.^66,67 However, drug resistance significantly limits its efficacy and remains a major challenge in colorectal cancer treatment.⁶⁸ Mechanisms of oxaliplatin resistance include enhanced DNA repair, evasion of apoptosis, activation of NF-_KB signaling, and altered drug transport.⁶⁹ Furthermore, O-GlcNAcylation is a unique form of post-translational protein modification involving the attachment of a single N-acetylglucosamine molecule to serine or threonine residues. This modification responds dynamically to cellular stress, hormonal changes, or nutrient availability by reversible addition or removal of sugar moieties on proteins. Thousands of nuclear and cytoplasmic proteins have been shown to undergo O-GlcNAcylation, which influences transcription, translation, signaling, the cell cycle, and other physiological processes.⁷⁰ It is increasingly recognized for its role in diabetes, neurodegeneration, cardiovascular disease, cancer, and has potential in diagnostics and therapeutics. KIAA1199 promotes O-GlcNAcylation of proteins via bridging O-GlcNAc transferase and substrate protein.⁵⁷ A study of Hua et al demonstrated that KIAA1199 is upregulated in oxaliplatin-resistant colorectal cancer cells compared to parental cells. KIAA1199 prevents apoptosis by alleviating endoplasmic reticulum (ER) stress via enhanced protein O-GlcNAcylation.³⁵ Furthermore, KIAA1199 sustains EMT and promotes colorectal cancer metastasis by O-GlcNAcylation of SNAI1.³⁵ It also acts as an immune suppressor, enabling colorectal cancer cells to escape immune surveillance,^71,72 and contributes to immunotherapy resistance by suppressing pyroptosis through the DNMT1/GSDME pathway.³⁶

Sorafenib is the first targeted therapy approved for advanced hepatocellular carcinoma. It inhibits tumor cell proliferation mainly via targeting the Raf/MEK/ERK signaling pathway and exerts antiangiogenic effects through inhibition of VEGFR-2/3 and PDGFR-β tyrosine kinases.⁷³ Although sorafenib has shown clinical benefit in hepatocellular carcinoma, long-term exposure frequently results in acquired drug resistance.^74,75 A study by Xu et al demonstrated that KIAA1199 expression was significantly elevated in both sorafenib-resistant hepatocellular carcinoma cell lines (in vitro) and xenograft models (in vivo). KIAA1199 promotes sorafenib resistance by enhancing the migratory and invasive capabilities of hepatocellular carcinoma cells.³⁷ Additionally, KIAA1199 contributes to sorafenib resistance and cell migration through modulation of the EGF-induced EMT process.³⁷ Furthermore, a study by Liu et al. demonstrated that KIAA1199, closely associated with lung metastasis, promoted pre-metastatic niche formation by increasing lung matrix stiffness and upregulated serum KIAA1199 was indicative of lung fibrotic changes severity in patients with hepatocellular carcinoma-lung metastasis.⁷⁶ Pirfenidone, an inhibitor of the TGF-β signaling pathway,^77-79 inhibits KIAA1199/TGF-β1/Smad signaling pathway and reduces lung metastases stiffening⁷⁶; Especially, pirfenidone in combination with sorafenib effectively suppresses the incidence of lung metastasis compared with sorafenib alone.⁷⁶ These findings suggest that KIAA1199 may serve as a novel therapeutic target for overcoming sorafenib resistance and inhibiting metastasis in hepatocellular carcinoma.

Paclitaxel remains a cornerstone in the treatment of advanced non-small cell lung cancer.^80,81 However, the development of paclitaxel resistance severely reduces its therapeutic efficacy. Mechanisms contributing to this resistance include upregulation of ATP-binding cassette (ABC) transporters, activation of pro-survival signaling pathways, induction of EMT,⁸² and dysregulation of epigenetic regulators.⁸³ Recent studies have shown that ALKBH5 expression is reduced in paclitaxel-resistant non-small cell lung cancer cell.³⁸ Overexpression of ALKBH5 in these resistant cells suppresses proliferation, increases paclitaxel sensitivity, and reverses EMT.³⁸ Importantly, KIAA1199 is a downstream target of ALKBH5, and the ALKBH5/KIAA1199 axis plays a pivotal role in modulating the EMT process suggesting that KIAA1199 regulates cancer cell sensitivity to paclitaxel in non-small cell lung cancer.³⁸ Furthermore, a study by Shen et al. demonstrated that in small cell lung cancer, KIAA1199 expression positively correlates with IC₅₀ values of chemotherapeutic agents as cisplatin, etoposide…, and KIAA1199 functions as an adaptor protein to interact with SRC and YAP enhancing their activation and nuclear signaling activity therefore combination of dasatinib (SRC inhibitor) or verteportin (YAP inhibitor) and cisplatin or etoposide displayed excellent synergistic antitumor effect in vitro and in vivo, suggesting KIAA1199/SRC/YAP complex is a potential strategy for small cell lung cancer patients.⁸⁴

5-Fluorouracil (5-FU), a first-line chemotherapeutic agent for gastric cancer, inhibits cancer cell proliferation, migration, and invasion by promoting DNA damage-induced apoptosis.^85,86 Moreover, combining apatinib or ramucirumab with 5-FU produces synergistic effects in suppressing metastasis and proliferation via the VEGFR-2/AKT/ERK1/2 pathway.⁸⁷ ZNF281, a novel biomarker associated with chemotherapy response, also influences sensitivity to 5-FU through the Wnt/β-catenin signaling pathway.⁸⁷ KIAA1199 has been identified as a prognostic marker in locally advanced gastric cancer patients who receive postoperative adjuvant chemotherapy with S-1.³⁹ Knockdown of KIAA1199 suppresses proliferation, invasiveness, and enhances the sensitivity of gastric cancer cells to 5-FU.³⁹ Therefore, KIAA1199 represents a novel therapeutic target in the pharmacologic treatment of gastric cancer.

KIAA1199 and Prognosis of Cancer

Prognosis of cancer refers to the prediction and evaluation of the likely course of the disease, potential recovery, and survival duration. Clinically, prognosis is influenced by factors such as tumor size, stage, grade, lymph node involvement, patient age, and treatment response.^88,89 KIAA1199 has been identified as a significant indicator of high metastatic potential and poor prognosis across multiple cancer types, including breast,^40,41 cervical,⁴² cholangiocarcinoma,³³ pancreatic,³¹ colorectal,^16,43,44 gastric,^26,45 hepatocellular,^28,29 lung,^22,23 ovarian,^42,46,47 prostate,^30,48,49 papillary thyroid,^17,50 and brain cancer.⁵¹ Thus, KIAA1199 holds promise as a prognostic biomarker in human malignancies.

KIAA1199 is upregulated in invasive breast cancer specimens and in the highly invasive MDA-MB-231 cell line, whereas its expression is minimal in non-invasive MCF-7 cells.¹⁰ KIAA1199 levels are higher in breast cancer tissue than in adjacent normal tissue,⁴¹ and patients expressing KIAA1199 exhibit significantly shorter overall and disease-free survival compared to non-expressers. Contributing factors for KIAA1199 overexpression in breast cancer include TP53 mutation, DNA hypomethylation, and transcriptional regulation by EZH2, EGR1, and JUN.⁴¹ These findings support the role of KIAA1199 as both a prognostic and metastatic biomarker and as a potential therapeutic target.

KIAA1199 is aberrantly expressed in human papillomavirus (HPV)-infected cells and in clinical samples of cervical (pre)neoplastic lesions.⁴² It binds Plexin A2 and protects cells from Semaphorin 3A-induced apoptosis by promoting EGFR stability and signaling.⁴² As an EGFR-binding protein, KIAA1199 deficiency impairs EGF-dependent phosphorylation of Src, MEK1, and ERK1/2. KIAA1199 also promotes EGF-mediated EMT,⁴² characterizing it as an oncogenic protein induced by HPV infection and sustained NF-_KB activation, which transmits pro-survival and invasive signals via EGFR signaling.

KIAA1199 is overexpressed in cholangiocarcinoma, and higher levels are associated with shorter overall and disease-free survival.³³ KIAA1199 enhances tumor growth and metastasis in cholangiocarcinoma.³³ Additionally, expression of EMT-related components in the TGF-β pathway is significantly altered upon upregulation or silencing of KIAA1199.³³ These findings highlight KIAA1199 as a promising prognostic marker and therapeutic target in cholangiocarcinoma.

In pancreatic ductal adenocarcinoma, KIAA1199 expression is significantly higher than in adjacent non-tumor tissues.³¹ Patients with high KIAA1199 expression exhibit markedly shorter overall survival. Both KIAA1199 expression and The Union for International Cancer Control (UICC) stage are independent predictors of poor prognosis,³¹ suggesting that overexpression of KIAA1199 contributes to disease progression and reduced post-surgical survival.

In colorectal cancer, KIAA1199 expression has been extensively studied across different tumor stages. In normal colonic mucosa, protein expression is restricted to the lower portions of intestinal crypts areas of physiological Wnt activity but is markedly upregulated in adenomas,^90,91 colorectal cancer,⁹² and stage I–IV adenocarcinomas.⁹³ In stage III and combined stage II plus III cases, 5-year overall survival is significantly better in patients with low KIAA1199-expressing tumors compared to those with high expression.⁴³ Furthermore, KIAA1199 expression correlates with tumor invasion depth, TNM stage, and poor prognosis.⁴⁴ Silencing KIAA1199 suppresses colorectal cancer cell migration and invasion in vitro, and inhibits metastasis in vivo.¹⁶ These findings support KIAA1199 as a clinically relevant prognostic biomarker and therapeutic target in colorectal cancer.

KIAA1199 is highly expressed in gastric cancer and has been associated with prognosis and lymph node metastasis.²⁶ KIAA1199 is also significantly upregulated in gastric cancer and is linked to disease progression.⁹⁴ High KIAA1199 expression is more common in advanced stages and correlates with poorer outcomes.⁹⁵ Furthermore, patients with high KIAA1199 levels have significantly shorter overall survival than those with low expression,⁴⁵ supporting its role as a prognostic biomarker in gastric cancer.

KIAA1199 expression is significantly elevated in hepatocellular carcinoma tissues compared to adjacent non-tumor tissues.^28,29 High KIAA1199 levels are associated with reduced disease-free and overall survival.²⁸ Its expression also correlates with larger tumor size and metastasis.²⁹ In vitro, KIAA1199 knockdown reduces cell proliferation and migration, while in vivo, it suppresses tumorigenesis and lung metastasis.²⁹ These findings suggest that KIAA1199 is a biomarker of poor prognosis in hepatocellular carcinoma .

In non-small cell lung cancer, KIAA1199 expression is significantly higher in tumor tissues than in normal lung tissue.²² Its high expression is associated with poor differentiation, lymph node metastasis, and advanced nodal stage.¹⁹ Elevated KIAA1199 levels predict poorer overall survival.^22,23 Mechanistically, KIAA1199 modulates EMT by affecting the expression of EMT markers, transcription factors, and signaling pathways.²³ Specifically, KIAA1199 promotes invasion and migration through PI3K-Akt–mediated EMT, establishing it as an independent prognostic biomarker in non-small cell lung cancer.

In ovarian cancer, KIAA1199 expression is higher in tumor tissues than in normal ovaries.³² Its knockdown significantly impairs tumor cell proliferation, migration, and invasion.³² KIAA1199 induces chemoresistance and metastasis by activating the PI3K/AKT/mTOR pathway.^32,46 It also enhances VEGFA expression and MMP activity, facilitating angiogenesis and cell migration.³² Furthermore, ovarian cancer patients with low expression of KIAA1199 had a significantly higher 5-year survival rate than those with high expression; and the expression of KIAA1199, STAT3 and p-STAT3 increased after IL-6 stimulation showing that KIAA1199 is transcriptionally activated by IL6/STAT3 pathway; suggesting that KIAA1199 could be used as a poor prognosis factor and potential target in treatment.⁴⁷

KIAA1199 expression is minimal in normal prostate epithelial (PrEC) cells and non-invasive LNCaP prostate cancer cells.⁸ In contrast, it is markedly elevated in prostate cancer tissues and cells.^10,30,48 High KIAA1199 expression correlates with tumor stage, overexpression of hypoxia-inducible factor 1α (HIF-1α), and increased angiogenesis.³⁰ It promotes angiogenesis and vasculogenic mimicry through enhanced secretion.³⁰ Additionally, KIAA1199 facilitates anoikis resistance and metastasis by activating PDK4-dependent metabolic reprogramming.⁴⁸ Furthermore, the correlation between the KIAA1199 expression and clinicopathological characteristics was analyzed, showing a positive correlation with the clinical prostate cancer stages (I + II vs III + IV, P = 0.0025) and the metastatic prostate PC-3 and DU145 cells exhibited the highest expression level among several well-known cell lines with varying metastatic potential (RWPE-1, LNCaP, 22RV1, PC-3, and DU145).⁴⁹ These findings support that KIAA1199 could be used as a poor prognosis factor and potential target in treatment of prostate cancer.

In papillary thyroid carcinoma, KIAA1199 expression is significantly upregulated in papillary thyroid carcinoma tissue compared with normal tissue.^17,50 Papillary thyroid carcinoma cells (TPC-1, KTC-1, CAL62, K1) showed higher expression of KIAA1199 than Htori-3 cells.⁵⁰ Additionally, KIAA1199 expression is positively correlated with more advanced clinicopathological characteristics.^17,50 KIAA1199 promotes cancer cell migration and invasion, and its silencing suppresses these functions by inhibiting EMT both in vitro and in vivo.^17,50 Furthermore, knockdown of KIAA1199 suppressed papillary thyroid carcinoma cell growth and metastasis through PDK4-mediated inactivation of STAT3/AKT/NF-kB.⁵⁰ These findings support that KIAA1199 could be used as a poor prognosis factor and potential target in treatment of thyroid cancer.

KIAA1199 is also highly expressed in brain metastases compared to adjacent brain stroma and non-brain metastatic lesions.⁴⁵ Its expression correlates with reduced survival, and high KIAA1199 levels in primary tumors are associated with rapid metastatic progression to the brain.⁵¹ Thus, KIAA1199 serves as a potential prognostic biomarker and therapeutic target in brain metastasis.

KIAA1199 and Cancer Stem Cells

Cancer stem cells are a subpopulation of cancer cells that exhibit properties like normal stem or progenitor cells, including self-renewal and multilineage differentiation. Cancer stem cells drive tumor growth and heterogeneity, suggesting that cancer stem cells can differentiate through adaptation to the tumor microenvironment and in response to therapeutic pressures, thereby contributing to a heterogeneous tumor phenotype.⁹⁶

In colorectal cancer, KIAA1199 shows higher expression in metastatic CD44⁺ cancer stem cells than in adjacent non-tumorous tissue.¹⁶ Its expression positively correlates with the number of circulating tumor cells and an interstitial phenotype.¹⁶ KIAA1199 also maintains c-Myc protein levels through ERK1/2 signaling, conferring a metabolic advantage in selumetinib-resistant colorectal cancer organoids ex vivo. Knockdown of KIAA1199 sensitizes these organoids to MEK1 inhibition by reducing ERK1/2 activation and c-Myc expression.³⁴

Furthermore, KIAA1199 is highly enriched in brain metastasis–derived small extracellular vesicles and has been shown to promote pre-metastatic niche formation and cancer cell colonization in the brain by upregulating cytokine expression.⁵¹ As cells undergoing EMT acquire cancer stem cells-like properties,⁹⁷ and given that KIAA1199 strongly promotes EMT, its deficiency results in a dramatic reduction of the cancer stem cell pool (defined as CD44⁺/CD24^- cells). Moreover, sphere formation under stem cell culture conditions is significantly dependent on KIAA1199.^40,42 Collectively, this evidence highlights that the cancer stem cell population critically depends on KIAA1199.

Conclusion and Future Perspectives

KIAA1199 (also known as CEMIP or HYBID), a key member of the Human Unidentified Gene-Encoded (HUGE) database, is considered a novel regulator of chemoresistance, prognosis and cancer stem cells in various types of cancer. In the present review, we briefly summarize how the abnormal expression of KIAA1199 is significantly associated with chemoresistance, prognosis and cancer stem cell in human cancer.

Preclinical and clinical studies designed to evaluate different therapeutic strategies could improve the ability to treat human cancer patients by inhibiting KIAA1199 in combination with chemotherapy or targeted therapy. In addition, KIAA1199 could be utilized as a clinical regulator to control chemoresistance, prognosis and cancer stem cell (Figure 1). Overall, significant future advances in these areas of precision medicine targeting KIAA1199 could be clinically meaningful and enhance the treatment efficacy for human cancer.

Figure 1.

The Clinical Role of KIAA1199 in Human Cancer. KIAA1199 Regulates Several Hallmarks of Cancer as a Clinical Regulator to Control Chemoresistance, Prognosis and Cancer Stem Cells. β-Catenin Binds TCF/LEF to Drive KIAA1199 to Induce Higher Expression of KIAA1199 which is Responsible for Significant Activation of the Ras/Raf/MEK1/ERK1/2 Signaling Pathway in Regulation of Chemoresistance, Prognosis and Cancer Stem Cell

Footnotes

ORCID iD

Hong-Quan Duong

Author Contributions

HQD, TNLD and VLN conceived the concept and wrote the manuscript. TTPP, VTL, TND critically revised the manuscript for intellectual content. HQD organized and revised the final version of the manuscript. Data authentication is not applicable. All authors have read and approved the final manuscript.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Foundation for Science and Technology Development (NAFOSTED; grant no. 108.06-2020.03) (H.Q.D).

Declaration of Conflicting Interests

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

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