Tumorigenesis Of Cervical Cancer Research Articles

Circ_0042986 Presence Restrains Cervical Cancer Development via Upregulating PEG3 by Directly Targeting miR-582-3p.

The participation of circular RNAs (circRNAs) in carcinogenesis is widely established. Numerous circRNAs with aberrant expression in cervical cancer (CC) are identified by RNA sequencing, whereas the function of these circRNAs remains unclear. We thus aimed to unveil the effects and mechanisms of circ_0042986 in CC. Circ_0042986 with aberrant downregulation in CC was obtained from GSE10286 dataset. qPCR and western blotting were employed for the detection of circ_0042986, miR-582-3p, and paternally expressed 3 (PEG3) expressions. EdU assay, colony formation assay, wound healing assay, transwell assay, tube formation assay, and flow cytometry assay were applied for functional analyses. The potential binding site was ensured by dual-luciferase reporter analysis, and their binding relationship was verified by pull-down assay. The transplanted tumor models were constructed for in vivo function verification of circ_0042986. Our findings exposed that the downregulation of circ_0042986 was verified in clinical CC samples. Circ_0042986 overexpression largely attenuated CC cell growth, invasiveness, angiogenesis, and survival. MiR-582-3p was targeted by circ_0042986, and the inhibitory roles of circ_0042986 presence were partly abolished by miR-582-3p enrichment. MiR-582-3p combined with PEG3, and circ_0042986 increased PEG3 expression via decoying miR-582-3p. The interaction between miR-582-3p and PEG3 on CC cell functions was confirmed, evidenced by the reversal effects of PEG3 knockdown on miR-582-3p deficiency-inhibited cancer cell malignant behaviors. Circ_0042986 overexpression also limited tumorigenesis of CC in animal models. In summary, circ_0042986 overexpression decoyed miR-582-3p to increase PEG3 expression, thereby blocking the malignant progression of CC.

METTL3 potentiates progression of cervical cancer by suppressing ER stress via regulating m6A modification of TXNDC5 mRNA.

N6-methyladenosine (m6A) is the most abundant chemical modification on mRNA and plays significant roles in many bioprocesses. However, the functions of m6A on cervical cancer (CC) tumorigenesis remain unclear. Here we found methyltransferase-like 3 (METTL3), a core member of the m6A methyltransferase family, was greatly upregulated as an independent prognostic factor in CC. Mechanistically, the transcription factor ETS1 recruited P300 and WDR5 which separately mediated H3K27ac and H3K4me3 histone modification in the promoter of METTL3 and induced METTL3 transcription activation. Furthermore, we identified TXNDC5 as a target of METTL3-mediated m6A modification through MeRIP-seq, and revealed that METTL3-mediated TXNDC5 expression relied on the m6A reader-dependent manner. Functionally, we verified that METTL3 promoted proliferation and metastasis of CC cells by regulating of TXNDC5 expression through in vitro and in vivo experiments. In addition, our study verified the effect of METTL3/TXNDC5 axis on ER stress. Taken together, METTL3 facilitates the malignant progression of CC, suggesting that METTL3 might be a potential prognostic biomarker and therapeutic target for CC.

Long Intergenic Non-Coding RNA LINC00885 Promotes Tumorigenesis of Cervical Cancer by Upregulating MACC1 Expression Through Serving as a Competitive Endogenous RNA for microRNA-432-5p [Expression of Concern

Expression of Concern for the article Long Intergenic Non-Coding RNA LINC00885 Promotes Tumorigenesis of Cervical Cancer by Upregulating MACC1 Expression Through Serving as a Competitive Endogenous RNA for microRNA-432-5p

15P N6-Methyladenosine modification of YY1 mRNA promotes cervical cancer tumorigenesis

Recent studies have indicated that N6-methyladenosine (m6A) methylation modification and regulators play a critical role in human cancers. However, the possible functions of m6A and its regulators on cervical cancer (CC) tumorigenesis are still unclear. This study explored the function and mechanism of METTL3 (methyltransferase-like 3) and its downstream target oncogenes in CC.

Cancer Stem Cells and Their Possible Implications in Cervical Cancer: A Short Review.

Cervical cancer (CC) is the fourth most common type of gynecological malignancy affecting females worldwide. Most CC cases are linked to infection with high-risk human papillomaviruses (HPV). There has been a significant decrease in the incidence and death rate of CC due to effective cervical Pap smear screening and administration of vaccines. However, this is not equally available throughout different societies. The prognosis of patients with advanced or recurrent CC is particularly poor, with a one-year relative survival rate of a maximum of 20%. Increasing evidence suggests that cancer stem cells (CSCs) may play an important role in CC tumorigenesis, metastasis, relapse, and chemo/radio-resistance, thus representing potential targets for a better therapeutic outcome. CSCs are a small subpopulation of tumor cells with self-renewing ability, which can differentiate into heterogeneous tumor cell types, thus creating a progeny of cells constituting the bulk of tumors. Since cervical CSCs (CCSC) are difficult to identify, this has led to the search for different markers (e.g., ABCG2, ITGA6 (CD49f), PROM1 (CD133), KRT17 (CK17), MSI1, POU5F1 (OCT4), and SOX2). Promising therapeutic strategies targeting CSC-signaling pathways and the CSC niche are currently under development. Here, we provide an overview of CC and CCSCs, describing the phenotypes of CCSCs and the potential of targeting CCSCs in the management of CC.

Oxymatrine induces anti-tumor response in cervical cancer by modulating circ_0008460/miR-197-3p/ribonucleotide reductase subunit M2 (RRM2)

ABSTRACT Oxymatrine (OMT) has exhibited an anti-cancer role in human cancers, including cervical cancer (CC). The dysregulated circular RNAs (circRNAs) are key regulators in cancer biology, and circ_0008460 was upregulated in CC. This study was performed to investigate the circRNA-based molecular mechanism for OMT in CC. RNA detection for circ_0008460, microRNA-197-3p (miR-197-3p), or ribonucleotide reductase subunit M2 (RRM2) was completed using reverse transcription-quantitative polymerase chain reaction assay. Cell behaviors were assessed by Cell Counting Kit-8 assay for cell viability, colony formation assay or Edu assay for cell proliferation, flow cytometry for cell apoptosis, and wound healing assay/transwell assay for migration/invasion. Protein expression examination was conducted using western blot. Dual-luciferase reporter assay and RNA pull-down assay were applied to confirm target binding. Tumor xenograft assay was performed for OMT research in vivo. OMT induced circ_0008460 downregulation in CC cells. OMT-induced inhibitory effects on cell growth, migration, and invasion but promoting effect on cell apoptosis were attenuated by circ_0008460. Circ_0008460 directly interacted with miR-197-3p, and OMT inhibited malignant behaviors of CC cells via mediating circ_0008460/miR-197-3p axis. RRM2 acted as a target for miR-197-3p and circ_0008460 affected the RRM2 level through absorbing miR-197-3p. OMT upregulated miR-197-3p to inhibit RRM2 expression to impede CC cell development. CC tumorigenesis was suppressed by OMT via targeting circ_0008460/miR-197-3p/RRM2 axis in vivo. These results suggested that OMT restrained CC cell progression in vitro and tumor growth in vivo by downregulating circ_0008460 to mediate miR-197-3p/RRM2 axis.

Like Brothers in Arms: How Hormonal Stimuli and Changes in the Metabolism Signaling Cooperate, Leading HPV Infection to Drive the Onset of Cervical Cancer.

Despite all precautionary actions and the possibility of using vaccinations to counteract infections caused by human papillomaviruses (HPVs), HPV-related cancers still account for approximately 5% of all carcinomas. Worldwide, many women are still excluded from adequate health care due to their social position and origin. Therefore, immense efforts in research and therapy are still required to counteract the challenges that this disease entails. The special thing about an HPV infection is that it is not only able to trick the immune system in a sophisticated way, but also, through genetic integration into the host genome, to use all the resources available to the host cells to complete the replication cycle of the virus without activating the alarm mechanisms of immune recognition and elimination. The mechanisms utilized by the virus are the metabolic, immune, and hormonal signaling pathways that it manipulates. Since the virus is dependent on replication enzymes of the host cells, it also intervenes in the cell cycle of the differentiating keratinocytes and shifts their terminal differentiation to the uppermost layers of the squamocolumnar transformation zone (TZ) of the cervix. The individual signaling pathways are closely related and equally important not only for the successful replication of the virus but also for the onset of cervical cancer. We will therefore analyze the effects of HPV infection on metabolic signaling, as well as changes in hormonal and immune signaling in the tumor and its microenvironment to understand how each level of signaling interacts to promote tumorigenesis of cervical cancer.

Deregulation of PiwiL1 and associated RNAs in cervical cancer: is HPV oncogene responsible?

Although HPV infection is the major cause of tumorigenesis in cervical cancer; interestingly it has been noted that HPV infection does not always lead to cervical cancer. This suggests that there could be some unknown factor that directly or indirectly interacts with these HPV oncoproteins leading to tumorigenesis. Our study aims to understand whether any correlation exists between the Piwi homologs with HPV oncoproteins in cervical cancer. To begin with, the expression pattern of Piwi proteins were evaluated in cultured cervical cancer (C33A, SiHa, and CaSki) cell lines. We observed that all the Piwi variants were differentially expressed in all the selected cervical cancer cell lines with PiwiL1 showing the highest expression in CaSki cells, suggesting a positive correlation with HPV oncoproteins. On investigating this correlation further, we found that PiwiL1 was co‐expressed and physically interacted with HPV oncoproteins E6 and E7. Not only E6 and E7 physically interact with PiwiL1, but also accentuated its expression when over‐expressed in HaCaT cells. Since PiwiL1 protein is known for its overexpression in many cancers, we wanted to know how this molecule is regulated in cancer. For this, we have carried out an in silico analysis of the PiwiL1 promoter to find the possible binding TFs using multiple online tools such as Alibhabha, AllegenPromo, and TFsitescan. We further shortlisted the TFs based on their function in cancer, interestingly we found both p53 and E2F in the list. Further analysis of these selected factors suggested that PiwiL1 promoter activity was significantly upregulated in the presence of E2F, whereas it was downregulated with p53. The binding of these transcription factors and their differential regulation of PiwiL1 promoter could be one of the reasons for its over‐expressed status in cancer. In addition to this, it is also known that the Piwi‐piRNA complex act as guiding signals for factors that play a significant role in tumorigenesis. Therefore, we have constructed a pipeline to predict the piRNAs from a small RNA Sequencing Data (SRP119662) obtained from the NCBI database, we identified 2274 piRNAs from both control and tumor samples, out of this, only 9 piRNAs were found to be significantly differentially expressed compared to control. Even though in silico analysis predicted 6 piRNAs to be significantly upregulated and 3 piRNAs to be significantly downregulated, the qPCR analysis was not entirely in accordance to the prediction. Out of the 3 down‐regulated piRNAs, hsa_piR_007863 showed elevated levels in CaSki in comparison to HaCaT while hsa_piR_002320 which was predicted to be upregulated in tumor showed lower expression. Our preliminary data suggest that PiwiL1 protein and associated piRNAs may have an important role in HPV‐associated tumorigenesis, whose exact molecular mechanism needs to be further evaluated.

Down-regulated Circ_0000190 promotes cervical cancer by facilitating the activity of proto-oncogene protein EIF4E

ABSTRACT Circular RNAs (circRNAs), a new class of non-coding RNAs, have been recently confirmed to regulate cell development, functions and certain types of pathological responses. In addition, it has been proved that circ_0000190 can serve as a tumor suppressor in several cancers. However, the underlying mechanism and biological functions of it in cervical cancer (CC) remain to be revealed. In our study, relative expression of indicated molecules was detected by RT-qPCR analysis. Loss-of-function and gain-of-function experiments were conducted to detect cell functions. Mechanism experiments including RIP assay, luciferase reporter assay and pull down assay were applied to verify the interaction among the indicated molecules. Overexpressed circ_0000190 attenuated CC progression in vitro and in vivo. Circ_0000190 functioned through the modulation of miR-1252-5p/EIF4EBP2 axis. Rescue experiments found that miR-1252-5p overexpression or EIF4EBP2 knockdown could reverse the influence on CC cells caused by circ_0000190 overexpression. Interestingly, it was found that EIF4EBP2 could bind to proto-oncogene eIF4E and prevent eIF4E from forming into complex and functioning. Circ_0000190 served as a tumor suppressor in CC and down-regulated circ_0000190 expression could weaken the binding ability of EIF4EBP2 to eIF4E thus leading to CC tumorigenesis. In our investigation, a novel tumor suppressive gene circ_0000190 was recognized, which could be treated as a promising biomarker for the diagnosis of CC.

Circ_0009035 regulates the progression of cervical cancer by targeting miR-1305/CREBRF axis.

Circular RNAs (circRNAs) have a crucial role in the occurrence of many diseases, such as tumors. Yet the roles of circ_0009035 (circRACGAP1) in cervical cancer are not fully characterized. The expression levels of circRACGAP1, miR-1305 and cAMP-responsive element-binding protein 3 regulatory factor (CREBRF) were detected by using real-time quantitative PCR or western blot. Cell counting kit-8 assay, 5-ethynyl-2'-deoxyuridine, colony formation assay, transwell assay and tube formation assay were used to detect cell proliferation, migration and invasion and angiogenesis, respectively. Flow cytometry assay was used to analyze the cell apoptosis. Dual-luciferase reporter assay and RNA immunoprecipitation assay were performed to analyze the targeting about miR-1305 and circ_0009035 or CREBRF. Xenograft model was built to study the role of circ_0009035 in vivo. Immunohistochemistry was used to detect the expression of Ki67, epithelial cadherin and vimentin. First, we found that circ_0009035 expression was significantly upregulated in tumor cells and tissues; second, knockdown of circ_0009035 could inhibit cell proliferation, migration and invasion and promote cell apoptosis. Subsequently, circ_0009035 was found to be able to target miR-1305, and the expression of miR-1305 in tumor tissues and cells was significantly lower. MiR-1305 inhibitor could restore cell-related progression of cervical cancer inhibited by si-circ_0009035. Finally, miR-1305 could target CREBRF, and circ_0009035 could regulate CREBRF expression by targeting miR-1305, thereby affecting cervical cancer tumorigenesis. In summary, our study confirmed that circ_0009035 could influence the development of cervical cancer through the targeted regulation of miR-1305/CREBRF.

Circ_0000263 facilitates the proliferation and inhibits the apoptosis of cervical cancer depending on the regulation of miR-1179/ABL2 axis.

Circular RNA (circRNA) has been reported to participate in the progression of cervical cancer (CC). Studies on the role and mechanism of circ_0000263 in CC are limited, and more studies are needed. The expression of circ_0000263, microRNA (miR)-1179 and ABL proto-oncogene 2 (ABL2) mRNA in tissues and cells was analyzed by quantitative real-time PCR. The proliferation and apoptosis of CC cells were determined using cell counting kit 8 assay, Edu assay, colony formation assay and flow cytometry. The protein expression of proliferation markers, apoptosis markers and ABL2 was detected by western blot analysis. The interaction between RNAs was estimated via dual-luciferase reporter assay. Xenograft models were applied to explore the effect of circ_0000263 knockdown on CC tumorigenesis. Circ_0000263 was highly expressed in CC tumor tissues. Silencing of circ_0000263 suppressed CC cell proliferation and increased apoptosis. Circ_0000263 served as a sponge for miR-1179, and miR-1179 inhibitor reversed the regulation of si-circ_0000263 on CC cell proliferation and apoptosis. ABL2 could be targeted by miR-1179, and circ_0000263 could sponge miR-1179 to regulate ABL2. Overexpression of ABL2 reversed the anti-proliferation and pro-apoptosis roles of miR-1179 in CC cells. In addition, circ_0000263 knockdown reduced CC tumor growth by miR-1179/ABL2 axis. In brief, the results demonstrated that circ_0000263 exerted an oncogene role in CC, which suggested that circ_0000263 might be a promising therapeutic target for CC.

Significance of Altered Fatty Acid Transporter Expressions in Uterine Cervical Cancer and Its Precursor Lesions.

High-risk human papilloma virus (HR HPV) infection is a major factor leading to the development of uterine cervical cancer. Data suggest that alterations in lipid metabolism are related to the pathogenesis of cervical cancer. Specifically, the uptake of exogenous fatty acids and their intracellular storage in lipid droplets enables cancer cells to survive and adapt to the changing tumor environment. We compared the immunohistochemical expression of fatty acid transport protein 4 (FATP4), and cluster of differentiation 36/fatty acid translocase (CD36/FAT) in normal cervical epithelium, low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), and squamous cell carcinoma (SCC) tissues of the uterine cervix. We also investigated the clinicopathological implications of these fatty acid transporters in SCC. Compared with that in normal cervical tissues, the expression of FATP4 was lower in LSIL (p=0.002), HSIL (p=0.006), and SCC (p=0.001). In contrast, CD36 expression was higher in SCC tissues than in normal cervical tissues (p<0.001). In normal cervical tissues, HR HPV-infected lesions exhibited a decrease in FATP4 (p<0.001) and an increase of CD36 (p=0.134), compared to those that were not infected with HR HPV. High CD36 expression was associated with a shorter recurrence-free survival (p<0.001). However, high FATP4 levels showed no significant correlation with the clinicopathological parameters of SCC. Altered expression levels of FATP4 and CD36 are unique features that might be related to HR HPV infection and promote tumorigenesis and progression of cervical cancer.

Methyltransferase-like 3 induces the development of cervical cancer by enhancing insulin-like growth factor 2 mRNA-binding proteins 3-mediated apoptotic chromatin condensation inducer 1 mRNA stability

ABSTRACT N6-methyladenosine (m6A) plays a critical role in the tumorigenesis of cervical cancer (CC). Here, we aimed to investigate the potential role of methyltransferase-like 3 (METTL3) in CC. Gene expression was determined via real-time quantitative polymerase chain reaction. Cellular functions were detected using colony formation, 5-ethynyl-2′-deoxyuridine (EdU), and Transwell assays. The interactions among METTL3, insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), and apoptotic chromatin condensation inducer 1 (ACIN1) were confirmed using the MeRIP and RIP assays. An in vivo assay was performed to verify the role of METTL3 in CC development. METTL3 is overexpressed in CC, and therefore, its knockdown inhibits the proliferation and migration of CC cells. Silencing METTL3 inhibits tumor growth in vivo. Moreover, a positive association was observed between METTL3 and ACIN1. METTL3 interacts with IGF2BP3 to promote the mRNA stability of ACIN1, the overexpression of which induces the aggressiveness of CC cells. METTL3 promotes ACIN1 mRNA stability to accelerate CC progression, implying that METTL3 is a promising biomarker in CC.

Distinct Roles of m5C RNA Methyltransferase NSUN2 in Major Gynecologic Cancers.

RNA methylation has recently emerged as an important category of epigenetic modifications, which plays diverse physiopathological roles in various cancers. Recent studies have confirmed the presence of 5-methylcytosine (m5C) modification on mammalian mRNAs, mainly modified by NOP2/Sun RNA methyltransferase family member 2 (NSUN2), but little is known about the underlying functions of m5C. Gynecologic cancers are malignancies starting from women’s reproductive organs. The prevalence of gynecologic cancers leads to a massive economic burden and public health concern. In this study, we investigated the potential biological functions of NSUN2 in common gynecologic cancers including cervical cancer, ovarian cancer, and endometrial cancer. Remarkably, distinct scenarios were found. The levels of NSUN2 did not show alteration in endometrial cancer, and in ovarian cancer, depletion of upregulated NSUN2 did not reduce carcinogenesis in cancer cells, suggesting that the upregulated NSUN2 might be an incidental effect. On the contrary, NSUN2 played a role in tumorigenesis of cervical cancer; depletion of upregulated NSUN2 notably inhibited migration and invasion of cancer cells, and only wild-type but not catalytically inactive NSUN2 rescued these malignant phenotypes of cancer cells. Mechanistically, NSUN2 promoted migration and invasion by leading to m5C methylation on keratin 13 (KRT13) transcripts, and methylated KRT13 transcripts would be recognized and stabilized by an m5C reader, Y-box binding protein 1 (YBX1). Collectively, these results not only displayed the nature of diversity among human malignancies, but also demonstrated a novel NSUN2-dependent m5C-YBX1-KRT13 oncogenic regulatory pathway.

The role of NFATc1/c-myc/PKM2/IL-10 axis in activating cervical cancer tumor-associated M2 macrophage polarization to promote cervical cancer progression

Nuclear factor of activated T cells 1 (NFATc1) is mainly expressed in tumor microenvironment, especially in macrophages. However, whether NFATc1 is involved in the polarization of tumor associated macrophages (TAMs) and tumor progression in cervical cancer (CC) remains unclear. Immunofluorescence staining was used to detect the expression of CD68 and NFATc1 in CC tissues or adjacent normal tissues of patients. RT-qPCR, flow cytometry, ELISA, and inhibitors treatment were used to observe the effect of NFATc1 on TAMs polarization. Clonal formation, scratch, and transwell assays were used to examine the effects of NFATc1-transfected macrophages or NFATc1-transfected TAM on tumor proliferation, migration, and invasion. Further, a xenograft model was established to confirm the roles of NFATc1+ TAM in CC tumorigenesis. NFATc1+CD68+/CD68+ TAMs ratio was significantly increased in CC tissues compared with the normal tissue, and NFATc1+ TAM showed an M2-like TAM subtype. NFATc1 induced macrophages to secrete IL-10, which further induced M2 polarization of macrophages. Mechanically, the c-myc-PKM2 pathway mediated the expression of IL-10 in NFATc1-induced macrophages. Functionally, NFATc1 induced M2 macrophages promoted the proliferation, migration, and invasion of CC cells, and the knockout of NFATc1 in TAMs significantly inhibited the tumor-promoting function of TAMs. Further, the tumorigenesis test in nude mice confirmed that NFATc1+ TAM promoted the tumorigenicity of CC cells in vivo. In conclusion, NFATc1 mediated IL-10 secretion by regulating the c-myc/PKM2 pathway, thereby inducing M2 polarization of TAMs and promoting the progression of CC.

HDAC10 Inhibits Cervical Cancer Progression through Downregulating the HDAC10-microRNA-223-EPB41L3 Axis

Background Although the tumorigenesis of cervical cancer (CC) has been widely investigated and recognized, the study of the systematic impact of histone deacetylase 10 (HDAC10), microRNA, and downstream molecular mechanisms in CC is still limited. Herein, cervical cancer, precancer lesions, and normal cervical tissues were collected to test the expression level of HDAC10, miR-223, and EPB41L3. The mechanism of HDAC10, miR-223, and EPB41L3 was interpreted in cervical cancer cells after HDAC10, miR-223, or EPB41L3 expression was altered. Results HDAC10 was poorly expressed in cervical cancer and precancer lesions, while miR-223 was highly expressed in cervical cancer. HDAC10 bound to miR-223, and miR-223 targeted EPB41L3. HDAC10 depressed the invasion property and tumorigenesis of cervical cancer via downregulating miR-223 and subsequently targeting EPB41L3. Conclusion The study clarifies that HDAC10 inhibits cervical cancer by downregulating miR-223 and subsequently targeting EPB41L3 expression, which might provide a new insight for management upon cervical cancer and precancer lesions.

The sphingosine kinase inhibitor SKI-V suppresses cervical cancer cell growth.

Overexpression and/or overactivation of sphingosine kinase 1/2 (SphK1/2) is important for tumorigenesis and progression of cervical cancer. The current study examined the potential activity and signaling mechanisms of SKI-V, a non-lipid small molecule SphK inhibitor, against cervical cancer cells. In different primary and immortalized cervical cancer cells, SKI-V exerted significant anti-cancer activity by inhibiting cell viability, colony formation, proliferation, cell cycle progression and cell migration. Significant apoptosis activation was detected in SKI-V-treated cervical cancer cells. Significantly, SKI-V also provoked programmed necrosis cascade in cervical cancer cells, as it induced mitochondrial p53-cyclophilin-D-adenine nucleotide translocator-1 (ANT1) complexation, mitochondrial membrane potential collapse, reactive oxygen species production and the release of lactate dehydrogenase into the medium. Further, SKI-V blocked SphK activation and induced ceramide accumulation in primary cervical cancer cells, without affecting SphK1/2 expression. SKI-V-induced cytotoxicity in cervical cancer cells was largely inhibited by sphingosine-1-phosphate or the SphK1 activator K6PC-5, but was sensitized by adding the short-chain ceramide C6. Moreover, SKI-V inhibited Akt-mTOR (mammalian target of rapamycin) activation in primary cervical cancer cells, and its cytotoxicity was mitigated by a constitutively-active Akt. In vivo, daily intraperitoneal injection of SKI-V significantly inhibited subcutaneous primary cervical cancer xenograft growth in nude mice. Together, the SphK inhibitor SKI-V suppresses cervical cancer growth in vitro and in vivo.

ARID1A-mutated cervical cancer depends on the activation of YAP signaling.

Cervical cancer is a prevalent female malignancy with poor survival rates. ARID1A is frequently mutated or deleted in a variety of tumors and YAP signaling is widely activated in human malignancies. Nevertheless, the mechanism of YAP signaling in ARID1A-mutated cervical cancer remains unknown. The cell viability was determined by MTT assay. The expression of ARID1A, YAP1 and CTGF were evaluated by western blot. The cell proliferation was detected by colony formation. The bioinformatics analysis suggested that mutation of ARID1A was associated with the activation of YAP1 signaling. In addition, knockdown of YAP1 inhibited ARID1A-mutated cervical cancer cells growth. Verteporfin is an inhibition of YAP1 signaling. Interestingly, knockdown of ARID1A decreased ARID1A-wildtype cervical cancer cells resistance to verteporfin. Meanwhile, overexpression of ARID1A increased ARID1A-mutated cervical cancer cells resistance to verteporfin. Similarly, blocking YAP1 signaling inhibited the tumor formation caused by ARID1A-mutated cervical cancer cells in vivo. Inhibition of YAP1 signaling suppresses ARID1A-mutated-induced tumorigenesis of cervical cancer, providing a novel therapeutic strategy for cervical cancer.

MACC1 regulates the AKT/STAT3 signaling pathway to induce migration, invasion, cancer stemness, and suppress apoptosis in cervical cancer cells

ABSTRACT Cervical cancer (CC) ranks as the second most frequent tumor in women, and CC stem cells have been vital in the tumorigenesis of CC. Recently, the metastasis- associated in colon cancer 1 (MACC1) gene was proven to be a promising biomarker of CC. However, the role and mechanism of MACC1 in CC remain undetermined. Expressions of MACC1 were estimated by qRT-PCR, immunohistochemistry, and Western blot assays in cervical cancer tissues and cells. Three siRNAs were generated to knockdown expressions of MACC1 in CC cells. After knockdown of MACC1 or/and Colivelin treatment, cell migration, invasion, apoptosis, and stemness were evaluated through a series of functional experiments including Transwell, flow cytometry, Hoechst staining, and sphere-formation assays. MACC1 was found to express more highly in CC tissues in comparison with corresponding non-tumor tissues at both mRNA and protein levels. Functionally, the knocking- down of MACC1 significantly repressed migration and invasion, and induced apoptosis of CC cells. Also, knockdown of MACC1 was discovered to suppress sphere-formation of CC cells and downregulate OCT4 and Nanog. It was proved that knockdown of MACC1 had a significant blocking effect on the AKT/STAT3 pathway. In addition, we verified that treatment with the STAT3 activator (Colivelin) had significant reversal effects on the malignant behaviors of CC cells and CC stemness. Our study concluded that MACC1 might be a novel regulator of CC by regulating the AKT/STAT3 pathway to change the migration, invasion, apoptosis, and cancer stemness of CC cells.

The Basally Expressed p53-Mediated Homeostatic Function.

Apart from mutations in the p53 gene, p53 functions can be alternatively compromised by a decrease in nuclear p53 protein levels or activities. In accordance, enhanced p53 protein turnover due to elevated expression of the critical p53 E3 ligase MDM2 or MDM2/MDMX is found in many human cancers. Likewise, the HPV viral E6 protein-mediated p53 degradation critically contributes to the tumorigenesis of cervical cancer. In addition, growth-promoting signaling-induced cell proliferation is accompanied by p53 downregulation. Animal studies have also shown that loss of p53 is essential for oncogenes to drive malignant transformation. The close association between p53 downregulation and carcinogenesis implicates a critical role of basally expressed p53. In accordance, available evidence indicates that a reduced level of basal p53 is usually associated with disruption of homeostasis, suggesting a homeostatic function mediated by basal p53. However, basally expressed p53 under non-stress conditions is maintained at a relatively low abundance with little transcriptional activity, raising the question of how basal p53 could protect homeostasis. In this review, we summarize the findings pertinent to basal p53-mediated activities in the hope of developing a model in which basally expressed p53 functions as a barrier to anabolic metabolism to preserve homeostasis. Future investigation is necessary to characterize basal p53 functionally and to obtain an improved understanding of p53 homeostatic function, which would offer novel insight into the role of p53 in tumor suppression.