Published online Jun 28, 2026. doi: 10.3748/wjg.118822
Revised: March 8, 2026
Accepted: April 13, 2026
Published online: June 28, 2026
Processing time: 126 Days and 2.2 Hours
Hepatocellular carcinoma (HCC) is a top primary liver malignant tumor, and still is hard to control after invasive growth and spread have already occurred. A big part of its biological difference in properties still cannot get explanation on the molecule level. Transmembrane emp24 domain-containing protein 4 (TMED4) it is one cargo-trafficking protein that belongs to the p24/TMED family. Albumins inside this grouping take part in endoplasmic reticulum-Golgi carrying, and can change signal plans which are related to tumor action, hence the function of TMED4 in HCC has not been clearly given definition. Owing to the fact that nuclear factor kappa-B (NF-κB)/snail pathway has close connection with proliferation, movement ability, invasion capability, and epithelial-mesenchymal transition, hence it is a reasonable path that TMED4 may use it to produce effect on HCC cells.
To describe the expression situation of TMED4 in HCC cells, we therefore confirm whether the forced expression of TMED4 can change cell growth, migration and invasion ability, and we also check whether these appearance changes are accompanied by the change of expression quantity of NF-κB p65 and snail.
The abundance of TMED4 transcription product in LO2 cells and SMMC-7721 cells has been measured through the method of quantitative real-time polymerase chain reaction. Through plasmid transfection, we have constructed a TMED4 overexpression SMMC-7721 model, the empty vector is used as the control by us. The increment of cell number was assessed through cell counting kit-8 test at continuous time points. Transwell chambers that have no or have Matrigel covering were utilized to measure migration and invasion, respectively. We have carried out the operation of Western blot for the detection of the protein expressions of TMED4, NF-κB p65 and snail.
Endogenous TMED4 messenger RNA expression level in SMMC-7721 cells is lower than that in LO2 cells (P < 0.05). After the transfection operation, the group with TMED4 overexpression displayed an obvious elevation in TMED4 messenger RNA when compared with the control group (P < 0.05). Optical density numerical values went up through time in two groups, but the increase was made weaker in TMED4-overexpressing cell groups (P < 0.05). When we make comparison with the control group, the overexpression group was found to have smaller numbers of cells that had migrated and invaded (P < 0.05). The experiment which used Western blot method has discovered that in the cells which have overexpression of TMED4, the protein content of TMED4 and NF-κB p65 is higher, while snail expression level is lower (P < 0.05).
The overexpression of TMED4 has the ability to suppress the proliferation, migration and invasion of HCC cells, therefore it may restrain the biological behaviors of HCC through the regulation of NF-κB/snail signaling pathways.
Core Tip: The transmembrane emp24 domain containing protein 4 (TMED4) expression was lowered in hepatocellular carcinoma (HCC) SMMC-7721 cells when compared with normal LO2 cells. The artificial forced overexpression of TMED4 has obviously held down the proliferation, migration and invasion of HCC cells. From the mechanism perspective, TMED4 made nuclear factor kappa-B p65 have higher expression, and at the same time made snail have lower expression, hence this shows that it restrains malignant phenotypes through adjusting the nuclear factor kappa-B/snail signal axis. These result findings point out that TMED4 is one potential adjustor of HCC aggression capability, and also one candidate molecular target for hereafter treatment exploration.
- Citation: Hao FT, Geng ZM. Transmembrane emp24 domain-containing protein 4 regulates nuclear factor kappa-B/snail signaling to influence hepatocellular carcinoma cell behaviors. World J Gastroenterol 2026; 32(24): 118822
- URL: https://www.wjgnet.com/1007-9327/full/v32/i24/118822.htm
- DOI: https://dx.doi.org/10.3748/wjg.118822
Hepatocellular carcinoma (HCC) is the main histological type of original liver cancer and still takes up a great proportion of cancer-caused deaths in the whole world. Clinical treatment management has obtained promotion, especially for patients whose tumor bodies are discovered early enough for resection, transplantation, or local ablation, but the overall burden of this disease still stays at a high level. Numerous patients still get diagnosis only after the tumor has already obtained blood vessel invasion, inside-the-liver spread, or outside-the-liver transfer ability. This clinical manifestation reflects the biological complexity of HCC, hence, it is not one single starting lesion. Long-term virus hepatitis, liver sclerosis, metabolism damage, continuous inflammation and messy tissue mending all work together to cause liver cancer occurrence, but the molecule net which keeps disease going is still not completely clarified[1]. This gap has importance in practical aspects, because biomarkers which only mark the disease are not as useful as molecules which also make clear how tumor growth and spread are pushed forward.
One kind of molecules that has obtained increasing notice in recent years is the transmembrane emp24 domain (TMED) family, which is also called the p24 family. TMED proteins are single-pass transmembrane proteins that are widely distributed in eukaryotic cells, and they are most famous for their participation in cargo transport between endoplasmic reticulum and Golgi apparatus[2,3]. The function of theirs does not be confined to simple shuttling movement. Through the shaping of cargo selection, vesicle coming-into-being, membrane arrangement, and the sending of signaling parts, TMED-family proteins are able to affect the way cells make reaction to inner pressure and outside signals. This is the reason why trafficking proteins, which were once mainly regarded as housekeeping molecules, are now being thought again in the field of tumor biology. Inside the cells that become cancerous, even small changes of the transport inside the cell can change the display of receptors, the intensity of downstream signal transmission, and the equilibrium between cell multiplication and cell death.
The evidences which come from many kinds of tumor models tell us that TMED-family members have connections with clinical meaningful phenotypes. Many research reports have connected this gene family to alterations in cell proliferation, invasion process, cell apoptosis, and therapeutic reaction, hence, it implies that their biological functions go far beyond basic protein transportation[4,5]. In the liver cancer, the out-of-order expression of TMED-related molecules has already been recorded, and the lifted TMED5 messenger RNA (mRNA) has been connected with primary HCC and patient disease outlook[6]. The discoveries got from lung adenocarcinoma give extra support to a function of signal conduction, because TMED2 has been related to inflammatory adjustment by a mechanism connected with Toll-like receptor 4/nuclear factor kappa-B (NF-κB)[7]. Putting all together, these experimental results let us have the reasonableness to guess that TMED4 can also take part in the signal environment which forms the behavior of HCC. In the meanwhile, the currently existing academic documents have not given a definition regarding whether TMED4 plays a tumor-promoting or a tumor-restraining role in the occurrence and development of HCC.
The uncertainty which is around TMED4 has importance because HCC progression is controlled by phenotypes which directly decide clinical failure: Continuous proliferation, tissue infiltration, blood vessel invasion, and metastatic spread. The control of these processes is achieved by interweaved signal networks, which are not isolated one-line routes. Among these, the NF-κB path has obtained long-standing attention because it connects inflammatory stimulation with transcription programs which affect survival, growth, movement, and tolerance to pressure. Snail, which is a transcription factor connected with epithelial-mesenchymal transition, is another molecule that is deeply involved in the conversion of invasion. When the activity of snails is kept going, the characteristics of epithelium are decreased, and the behavior of migration thus becomes more obvious. In many tumor related situations, the functional link between NF-κB and snail has been already reported, therefore this indicates that pathway interaction on this level may be one method through which HCC cells obtain a more aggressive biological character[7].
Under this kind of background, this current research was designed by us for answering one relatively concentrated question. We firstly have compared the expression of TMED4 in LO2 cells which come from normal liver and SMMC-7721 HCC cells. We afterward built a TMED4 over-expression SMMC-7721 model, thus the effect of TMED4 resume on proliferation, migration, invasion can be directly inspected. In the end, we have determined the expression quantities of NF-κB p65 and Snail protein, in order to probe whether the observed phenotype changes were accompanied by transformations in the NF-κB/snail-related signaling environment. Even though this design cannot give a complete mechanism diagram, it can make clear whether TMED4 has connection with aggressive conduct in HCC cells, and whether this connection is worthy of deeper follow-up research work.
The normal human liver cell strain LO2 and the HCC cell strain SMMC-7721 were bought from the Cell Bank of the Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences.
A TMED4 overexpression plasmid and the corresponding empty vector were constructed by Shanghai Sangon Biotech Co., Ltd. Lipofectamine® 2000 was utilized for plasmid transmission. RPMI-1640 culture medium, radio immunity precipitation experiment (RIPA) split solution, strengthened chemiluminescence reagent, and bicinchoninic acid protein measurement kit were gotten from commercial supply merchants. The first-grade antibody reagents which target TMED4, snail, NF-κB p65, and glyceraldehyde-3-phosphate dehydrogenase have been bought from Cell Signaling Technology (Danvers, MA, United States). The conventional quantitative real-time polymerase chain reaction (qRT-PCR) and microplate reading apparatus were provided by commercial producing factories.
LO2 and SMMC-7721 cells were underwent culture in RPMI-1640 culture medium which was added 10% fetal bovine serum, and were kept at 37 °C in a humid air environment that contained 5% carbon dioxide. The cells which are in the logarithmic growth phase have been chosen to be used for the follow-up experiments.
The entire RNA of total was extracted by using TRIzol reagent, and therefore it was then reverse-transcribed into complementary DNA. We utilized qRT-PCR to carry out the quantification of TMED4 transcript levels in LO2 cells, untreated SMMC-7721 cells, and transfected SMMC-7721 cells. Glyceraldehyde-3-phosphate dehydrogenase has acted as the internal reference gene. The sequences of primers were synthetized in accordance with works that were published before. The calculation of relative mRNA abundance was conducted by means of the 2-ΔΔCT method.
For the function experiments, SMMC-7721 cells were separated into two groups: One TMED4 overexpression group and one empty-vector control group. The TMED4 plasmid or corresponding control plasmid was transfected by Lipofectamine® 2000 according to the protocol that the manufacturer provided. The success of transfection was confirmed through the increment of TMED4 mRNA which was measured by the method of qRT-PCR.
The transfected SMMC-7721 cells have been planted into 96-well plates. On the prearranged time points, 10 μL of cell counting kit-8 solution was put into each well and incubation was kept going for 2 hours under the dark condition. Then, the optical density value was recorded at 450 nm at 0 hour, 1 hour, 2 hours, 3 hours, 4 hours, and 5 hours.
We used Transwell inserts that do not have Matrigel to carry out migration analysis, and as for invasion analysis, we used inserts that are coated with Matrigel. We put the cells into the upper chambers and then carried out culture for 48 hours. The cells which still stayed on the surface of upper membrane were taken away in a gentle way. The cells which had already passed through the membrane were fixed, dyed with crystal violet, and counted in five randomly selected microscope viewing areas.
We made extraction of protein from transfected cells by use of RIPA lysis buffer, and we did quantification before the electrophoresis. Equal quality of cracked liquid were separated through sodium dodecyl sulfate-polyacrylamide gel electrophoresis and moved onto polyvinylidene difluoride films. After blocking was finished, the membranes were incubated through the night at 4 °C with primary antibodies that aim at TMED4, snail, and NF-κB p65 (1:2000). Corresponding two-level antibodies (1:3000) were then added to incubate 1 hour under room temperature. The visualization of signals was completed by utilizing an enhanced chemiluminescence system.
We carried out the statistical processing by utilizing SPSS versions 23.0 and 25.0. The continuous variables are expressed in the form of mean ± SD. Comparisons between different groups were conducted by using the independent sample t examination. We have regarded a two-sided P value which is smaller than 0.05 as having statistical significance.
The qRT-PCR detection result showed that internal TMED4 mRNA expression level was obviously lower in SMMC-7721 cells than in LO2 cells (P < 0.05; Figure 1).
After the plasmid was delivered, the expression level of TMED4 mRNA in the overexpression group had an obvious increase when compared with the control group of empty vector, this confirms that the establishment of the cell model is successful (P < 0.05; Figure 2).
Optical density numerical values go up with time passing in two groups, therefore they point out that cell growth keeps going during the time we carry out observation. But, the increase of optical density numerical values was smaller in TMED4-overexpressing cells compared with control cells, this situation was in accordance with decreased proliferation activity after TMED4 recovery (P < 0.05; Figure 3).
Transwell experiment results indicated that the quantities of migrated and invaded cells are both smaller in the TMED4 overexpression group than that in the control group (P < 0.05; Figure 4).
The experiment of Western blot indicated that when TMED4 was overexpressed, it was accompanied by higher levels of TMED4 and NF-κB p65 proteins, along with lower expression of snail, when compared with that which was observed in the control group (P < 0.05; Figure 5).
HCC is still a disease in which the biological aggressiveness often decides the outcome. Although the monitor and cure have got better, recurrence, blood vessel attack, and transfer diffusion still are the main reasons for most death that appears in late-stage cases. Current existing reviews always stress that progress in HCC treatment will rely not only on improved therapeutic methods but also on a more clear cognition of the molecular systems that let tumor cells continue to live, adjust, and spread[8-10]. Because of this reason, molecules which take part in core cell processes and also show ability to change malignant behavior are worthy of careful research.
TMED family proteins belong to such category. They are in classical manner described as transport-connected proteins which function along the secretory pathway, yet that description only captures a part of their importance. Cargo transport process helps decide which receptors and signaling middle substances reach the correct intracellular space, how membrane constitution is kept, and how cells make responses to pressure or growth signals. From that perspective, transportation proteins can affect signal quality not less than signal proteins themselves do. Previous researches have already proved that TMED-family members make contribution to embryonic growth and cell steady-state maintenance, and multiple researches have connected them to malignant features in varied kinds of tumors[11-13]. The problem that has not been made clear until now is whether TMED4 possesses a significant function in HCC in particular, and if this holds, whether its influence is protective or promotive.
We first important discovery was that the abundance of TMED4 transcript in SMMC-7721 cells is lower than that in LO2 cells. This kind of rule indicates that the expression level of TMED4 possibly gets lower in the process of hepatocellular carcinogenesis or when tumor cells get a character of more aggressive tumor phenotype. This explanation does not have contradiction from existing research works, but it indeed puts emphasis on that the biological knowledge of TMED family is dependent on specific situation. Take breast cancer as an example, among them members like TMED2, TMED3, TMED4, and TMED9 have connection with clinicopathological features, and it is reported that TMED3 can promote proliferation, invasion, and cell cycle advancement[13,14]. Our research results walk another direction and hence indicate that TMED4 may not show same action in all different kinds of tissues. In liver-originated tumor cells, decreased TMED4 may indicate a condition that allows quicker growth and stronger movement capability instead of a condition that limits such behaviors.
The data about function give support to that explanation. When TMED4 was put again into SMMC-7721 cells, growth ability decreased, and both moving and entering were weakened. These changes have not only involved a sole information output. On the contrary, three connected malignant appearance types changed toward the same direction, therefore this enhances the opinion that TMED4 acts on a wider behavior plan instead of a single final result. This discovery is worthy of attention because molecules which at the same time affect growth and invasive action are frequently more connected with disease development than molecules connected with only one experimental measurement. The decrease of cell growth shows that the recovery of TMED4 may disturb the pathways which maintain proliferation or cell fitness, while the weaker moving and invasion mean that there is a simultaneous influence on movement-related programs and cell contact with the extracellular environment.
The mechanism-related part of this research was on purpose restricted, but it nevertheless provides hints. We have carried out examination on NF-κB p65 and snail for the reason that these molecules hold a core position in discussions about inflammatory signaling, invasive conversion, and epithelial-mesenchymal transition. NF-κB carries on integration of signals which come from cytokines, inflammatory stress, and growth-factor stimulation, therefore it can mold transcription programs that are related to proliferation, survival, and differentiation[15,16]. In the meantime, Snail is by many people extensively acknowledged to be a key transcription factor that has connection with epithelial-mesenchymal transition and metastatic behavior. Research works that were done before point out that the signaling which relates to NF-κB can have the function of stabilizing or increasing the activity of snail, therefore this is helpful for the process of invasion and spread[17,18]. This background lets the NF-κB/snail axis become a reasonable first pathway that people need to examine when TMED4 is in the restored situation.
Our experiment data indicated that TMED4 overexpression caused the increase of total NF-κB p65 protein content, and at the same time it decreased the expression of snail. The decrease of snail number accords with the seen lowering of migratory and invasive activity, hence therefore it matches the phenotypic data quite well. The increment of p65 is harder to explain within a simple open-close framework. The total amount of all protein does not necessarily reflect the activation degree of the pathway. The biological outcome of NF-κB signal transmitting relies on phosphorylated condition, nucleus entering, upstream inhibiting proteins, and cooperating with other transcript adjusting controllers, none of which was tested in this current research. Therefore, thus the current results can better be understood as the evidence which shows that TMED4 has an association with a change of the NF-κB/snail signaling environment, rather than the proof of simple canonical activation or suppression. This viewpoint is very important, because oversimplified explanation would therefore exaggerate the extent which the data can give support to.
Another useful enlightenment of the present results is that TMED4 may affect HCC cells via mechanisms related to intracellular transport instead of only through direct transcription regulation. If TMED4 has the function of changing cargo processing between endoplasmic reticulum and Golgi compartments, it may thus indirectly bring changes to the handling or position of receptors, adaptor proteins, or membrane components which provide input to inflammatory and motility-connected pathways. This kind of possibility can make TMED4 conform to the wider viewpoint of cancer biology, in which the problems of substance conveying and the problems of signal transmission are not two independent things, but are two sides of the same cell reconstruction process. The future work which aims at receptor turnover, subcellular localization, phosphorylation events, or pathway-rescue experiments would have usefulness for the clarification of this point.
This research also possesses shortcomings that it is necessary for us to clearly point out. All experiment works have been conducted in the in vitro environment, and they all depend on one single HCC cell strain. Although SMMC-7721 has already obtained widespread usage, a single model is not able to capture the molecular diversity that HCC possesses. This current design also paid attention to proliferation, migration, invasion, and the changes of selected proteins, but did not inspect apoptosis, cell-cycle distribution, epithelial-mesenchymal transition markers except for snail, or the transcription activity of NF-κB. Besides, no rescue strategy or pathway repressor was utilized to confirm whether the observed phenotypes directly rely on the NF-κB/snail background. These existing restrictions do not overturn the obtained results, but they therefore mean that the mechanism-based final conclusions hence should be kept with caution.
Even under those limitations, the research provides a helpful component to the comprehension of HCC cell biological characters. In SMMC-7721 cells, the expression level of TMED4 is decreased, and when one lets its expression return, this makes the cells have lower proliferation ability and lower invasion ability. The together change of NF-κB p65 and snail gives support to the view that TMED4 is connected to a signal situation related to tumor aggression degree. From the perspective of translation application, these research results are still in early stage, but they are not unimportant. Molecules which link intracellular substance transport with invasive action may finally provide useful information not just as biological markers but also as starting points for mechanism-based classification in hepatic carcinoma[19]. More research in extra HCC models, animal systems, and clinical samples will be needed before the treatment or diagnosis value of TMED4 can be evaluated with certain assurance.
To give the summary, the expression level of TMED4 in SMMC-7721 HCC cells is lower than that which is in LO2 cells. The re-occurrence expression of TMED4 held back cell proliferation, migration, and invasion in the environment outside the living body, and these effects were accompanied by changed NF-κB p65 and snail protein quantity levels. The existing findings support a restraining function for TMED4 in HCC cell aggressive behaviors, but more detailed mechanism research and verification in animal and clinical samples are still needed.
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