Wild-type P53 Research Articles

Comparative analysis of p53 protein expression in early-onset and later-onset colorectal cancers

Background: The global incidence of early onset colorectal cancer (CRC) is rapidly rising. However the reason for this and genomic characteristics of early onset CRC is largely unknown. p53 mutation is common in CRC and has been linked to an increased risk of early onset CRC. Methods: All CRC patients operated at Department of Surgical Oncology, NICRH, between October 1, 2021 and September 30, 2022 were included in this study. Demographic and clinical data and surgical findings were recorded. Histopathology and p53 immunohistochemistry (IHC) analysis was done. Patients were categorized in two groups – ‘Early onset’ (diagnosed before 50 years of age) and ‘Late onset’ (diagnosed at or after 50 years of age). p53 protein IHC status (Mutant or Wild type) and other clinicopathological features were compared between the two groups. Result: Out of 129 patients operated, 75 (58.14%) patients were in the early onset group. Compared to the late onset group, early onset patients had longer duration of symptoms (112.4 days vs. 88.7 days; p = .032), more peritoneal seedlings during surgery (14.7% vs. 1.9%, p = .011), and more poor differentiation (p = .062) and higher grades (p = .017) on histopathological analysis. Early onset patients had significantly more p53 mutation on IHC analysis than elderly ones (34.7% vs. 16.7%, p = .018). Age of onset showed no significance on either disease free survival (DFS) or overall survival (OS) in this study. On comparison of patients with either mutant (MT) or wild type (WT) p53 protein, those with MTp53 had more positive family history (20.0% vs. 3.2%, p=.004), higher levels of CEA (6.4 vs. 4.3, p = .028), higher pathological stage (p = .029), more chance of disease progression or recurrence during follow up (p=.035). Short term survival analysis showed patients with p53 mutation had significantly less DFS (p < .001) and OS (p = .001). Conclusion: Early onset CRC was more prevalent in this study, and was associated with significantly more p53 mutation than the elderly patients. The clinical application of p53 mutation analysis by IHC in all CRC cases, particularly in the early onset patients, should be evaluated. J Bangladesh Coll Phys Surg 2025; 43: 5-12

Side-stepping the guardian of the genome: current cancer therapeutics targeting mutant p53

Cancer therapies have attempted to target the transcription factor p53, a gene also described as the “guardian of the genome,” for decades. However, the approach has faced numerous barriers to clinical efficacy due to several factors: mutations in p53 occur in almost half of all human cancers, mutations are cancer-specific, and the associated genomic changes grant mutant p53 with oncogenic potential unique from that of wild-type p53. A host of new therapeutic agents have emerged that work to target mutant p53. These agents can broadly be classified into six categories: the viral approach, direct modifiers of the p53 pathway, epigenetic modifiers of the p53 pathway, synthetic lethal agents, structural reactivators, and immune activating vaccines. Even these strategies have been met with limited success. Bypassing p53 entirely may be the next avenue in cancer therapeutics to kill tumor cells regardless of p53’s mutation pattern.

Mutant p53 regulates a distinct gene set by a mode of genome occupancy that is shared with wild type.

To directly examine the interplay between mutant p53 or Mdm2 and wild type p53 in gene occupancy and expression, an integrated RNA-seq and ChIP-seq analysis was performed in vivo using isogenically matched mouse strains. Response to radiation was used as an endpoint to place findings in a biologically relevant context. Unexpectedly, mutant p53 and Mdm2 only inhibit a subset of wild type p53-mediated gene expression. In contrast to a dominant-negative or inhibitory role, the presence of either mutant p53 or Mdm2 actually enhances the occupancy of wild type p53 on many canonical targets. The C-terminal 19 amino acids of wild type p53 suppress the p53 response allowing for survival at sublethal doses of radiation. Further, the p53 mutant 172H is shown to occupy genes and regulate their expression via non-canonical means that are shared with wild type p53. This results in the heterozygous 172H/+ genotype having an expanded transcriptome compared to wild type p53 + /+.

Case report: Chemotherapy plus sintilimab for the treatment of gastroesophageal junction hepatoid adenocarcinoma with liver metastasis: a case study with literature review

ObjectiveTo elucidate the clinicopathological features and treatment of metastatic gastroesophageal junction hepatoid adenocarcinoma (GEJ HAC)using a case study and literature review.MethodsClinical presentation, results of histology and immunohistochemistry, and next-generation sequencing(NGS) in a patient with GEJ HAC metastasizing to the liver were reviewed. Chemotherapy (SOX or S-1) plus sintilimab was administered.ResultsA 65-year-old male patient with a history of hypertension was admitted to the hospital due to a one-week increase in serum AFP levels. There was a small intraluminal mass at the GEJ and a metastatic lesion in liver segment VIII, as well as enlarged perigastric and retroperitoneal lymph nodes. Tumor cells in both the GEJ and liver tissue exhibited a glandular shape with a nest-like adenoid structure. Immunohistochemical (IHC) analysis of the GEJ tissue showed positivity for AFP, CA19-9, CK7, CK20, MUC-1, P53 (wild type), Glypican-3, and HepPar-1, and negativity for Arginase-1, CD10, and Her-2. In the metastatic liver tissue, IHC testing demonstrated positivity for AFP, CD10, CK19, CK20, HepPar-1, MUC-1, Ki-67, and P53 (wild type), while CK7 was negative. The NGS report of GEJ mass indicated that the JAK2 and TP53 genes harbored missense mutations, while the MLH1, MSH2, MSH6, PMS2, ERBB2, EGFR, PIK3CA, APC, CTNNB1, CDH1, and DPYD genes were normal. The patient’s serum levels of CEA, CA19-9, and AFP were sharply decreased. The patient achieved a major pathological response (MPR) and remains in a progression-free stage.ConclusionsSintilimab-based chemotherapy has proven efficacy in achieving a MPR and maintaining a progression-free state for a patient with GEJ HAC that has metastasized to the liver.

Molecular classification of endometrial cancers (EC) and association with relapse-free survival (RFS) and overall survival (OS) outcomes: Ancillary analysis of GOG-0258.

Determine if molecular classification using mismatch repair (MMR) and p53 protein expression predicts recurrence-free survival (RFS) and overall survival (OS) in endometrial cancer (EC) patients treated with chemotherapy and radiation (CRT) versus chemotherapy (CT). GOG-0258, a phase III randomized trial (NCT00942357), compared CRT to CT. Immunohistochemistry assessed MMR and p53 status. Kaplan-Meier curves and adjusted Cox models analyzed survival outcomes by molecular subtype. ECs classified as deficient MMR (dMMR) (27%), p53 abnormal (p53abn) (24%), and p53 wild type (p53wt) (49%). p53abn were more frequent in patients that were older, Black, and had serous histology (p<0.001). Median follow up was 113months. Five-year RFS and OS were worse with p53abn (29% [Hazard Ratio (HR)=3.39 (95% Confidence Interval (CI): 2.34-4.91)] and 39% [HR=4.64 (95% CI: 3.16-6.79)] compared to those with p53wt (referent) (p<0.001). The five-year RFS and OS for dMMR cancers were (58% [HR=1.30 (95% CI: 0.85-1.97)] and 77% [HR=1.53 (95% CI: 0.99-2.36)] compared to those with p53wt (69% and 85%). After adjusting for age, gross residual disease, and treatment, p53wt improved RFS with CRT compared to CT in an exploratory analysis (77% vs 60%; HR=0.54 (95% CI: 0.32-0.94). The 5-year and 10-year OS rates were similar in CRT compared to CT in all subgroups. Molecular classification appears to be predictive and prognostic, with worse survival in those with p53abn tumors. In an exploratory analysis, p53wt appears to predict improved RFS, favoring CRT over CT. There was no difference in treatment efficacy based on molecular subtype for OS.

TP53 Wild-type, HPV-independent Anal Growth/(intra)Epithelial Lesion (ANGEL): a Potential Precursor of Anal Squamous Cell Carcinoma.

Human papillomavirus (HPV) underpins approximately 90% of squamous cell carcinomas (SCC) of the anus and perianal region. These tumors usually arise in association with precursor lesions such anal intraepithelial neoplasia/ high-grade squamous intraepithelial lesion (AIN 3/ HSIL), whereas a small subset of HPV-negative cancers may harbor mutations in TP53. Recently, vulvar lesions termed differentiated exophytic vulvar intraepithelial lesion/vulvar acanthosis with altered differentiated (DEVIL/VAAD) have been recognized as HPV-independent, TP53 wild-type precursors for vulvar carcinoma; however, analogous anal lesions have not been described. Cases of diagnostically challenging, TP53 wild-type HPV-negative anal squamous lesions with unusual histologic features including acanthosis and/or verrucous architecture were retrospectively identified. Lesions with koilocytic changes, lack of surface maturation, or significant cytologic atypia were excluded. HPV status was determined by immunohistochemistry for p16 and/or in situ hybridization for low- and high-risk strains, while TP53 status was assessed using immunohistochemistry and molecular studies in a subset of cases, with targeted molecular sequencing performed in three of these. All lesions (5/5) arose in men, ages ranging from 55 to 78 years (median: 65). Verrucous architecture was seen in 2/5 cases, 2/5 were predominantly acanthotic, and 1/5 had both verrucous and acanthotic growth. The lesions were characterized by hyperkeratosis (5/5), hypergranulosis (5/5), and cytoplasmic pallor of upper epithelial layers (2/5). All cases were negative for HPV and had wildtype p53 expression. Three cases with sufficient material for sequencing lacked alterations within the entire coding sequencing of TP53. Invasive SCC was concurrently present in 3/5 cases. In summary, verrucous and acanthotic HPV-independent TP53 wild-type squamous proliferations of the anal and perianal region, referred herein as ANGELs (anal growth/(intra)epithelial lesions), are pre-malignant lesions that have the potential to become invasive, as most of our cases demonstrated synchronous SCC.

Correlation between p53 immunoexpression and TP53 mutation status in extrapulmonary small cell neuroendocrine carcinomas and its association with patient survival.

Extrapulmonary small cell neuroendocrine carcinoma (EP-SCNC) is a rare malignancy with a poor prognosis. Despite its morphological similarity to lung small cell carcinomas, its oncogenesis remains uncertain. One hundred and seventy-one EP-SCNC were enrolled in a multicenter study, and all tissue samples underwent an immunohistochemical p53 analysis. One hundred twenty-five samples were molecularly analyzed using next-generation sequencing (NGS), comprising DNA and RNA analysis. p53 normal/wild type expression was detected in 68 cases (39.8%), whereas aberrant expression was detected in 103 cases (60.2%). Molecular TP53 alteration was detected in 92 out of 125 tumors (73.6%). The TP53 mutation was shown to be prognostic andassociated with shorter overall survival (p = 0.041). The multivariate analysis of p53 and TP53 mutational status found that it impacted overall survival relative to distinct sites of tumor locations (p = 0.004 and p = 0.001, respectively). Age did not influenced survival in the multivariate analysis of p53 and TP53 (p = 0.002; p < 0.001resp.). Among tumors with paired immunohistochemical and molecular results, 108 exhibited concordance between the immunohistochemical and molecular analysis, whereas 17 were discordant. Accordingly, p53 aberrant expression was tightly associated with a TP53 mutation (p < 0.001). In discordant cases, molecular analysis revealed no alteration in three tumors with p53 overexpression. In contrast, in 14 tumors with wild-type p53 expression, TP53 genetic alteration was detected. Possible causes of discordance are discussed in this manuscript. Furthermore, the incidence of aberrant p53 expression / TP53 molecular alteration was noticeably lower in EP-SCNC than in small-cell lung carcinomas. Therefore, in EP-SCNC, other driver mutations should be sought since personalized therapy can improve patient prognosis.

DNA Damage-Induced Ferroptosis: A Boolean Model Regulating p53 and Non-Coding RNAs in Drug Resistance.

The tumor suppressor p53, in its wild-type form, plays a central role in cellular homeostasis by regulating senescence, apoptosis, and autophagy within the DNA damage response (DDR). Recent findings suggest that wild-type p53 also governs ferroptosis, an iron-dependent cell death process driven by lipid peroxidation. Post-translational modifications of p53 generate proteoforms that significantly enhance its functional diversity in regulating these mechanisms. A key target in this process is the cystine/glutamate transporter (xCT), which is essential for redox balance and ferroptosis resistance. Additionally, p53-induced miR-34c-5p suppresses cancer cell proliferation and drug resistance by modulating Myc, an oncogene further influenced by non-coding RNAs like circular RNA NOTCH1 (CricNOTCH1) and long non-coding RNA MALAT1. However, the exact role of these molecules in ferroptosis remains unclear. To address this, we introduce the first dynamic Boolean model that delineates the influence of these ncRNAs and p53 on ferroptosis, apoptosis, and senescence within the DDR context. Validated through gain- and loss-of-function perturbations, our model closely aligns with experimental observations in cancers such as oral squamous cell carcinoma, nasopharyngeal carcinoma, and osteosarcoma. The model identifies crucial positive feedback loops (CricNOTCH1/miR-34c/Myc, MALAT1/miR-34c/Myc, and Myc/xCT) and highlights the therapeutic potential of using p53 proteoforms and ncRNAs to combat drug resistance and induce cancer cell death.

KRT20-/SATB2+/MCPyV+ Sinonasal Merkel Cell Carcinoma: A Detailed Immunohistochemical and In Situ Hybridization Study.

Merkel cell carcinoma (MCC) is an uncommon aggressive neoplasm, usually arising in sun-exposed skin of the head and neck. By immunohistochemistry, KRT20 and MCPyV positivity are found in about 90% and 80% of MCCs, respectively. Noteworthy, viral status in lip/oral cavity MCCs is poorly known. A 78-year-old male was referred presenting a tumor mass on the right maxilla four months ago. Computed tomography revealed an extensive osteolytic lesion in the right maxillary sinus extending into the orbit and nasal cavity and crossing the midline. Microscopy revealed large necrotic areas admixed by sheets of small, round cells with hyperchromatic nuclei exhibiting a '"salt and pepper" chromatin pattern, which showed immunopositivity for pan-KRT AE1/AE3, EMA, CD56, CD99 (weak), CD138, S100 (focal), vimentin (focal), synaptophysin, FLI1, INSM1, MCPyV, SATB2, and Ki-67 (MKI67 [40%]). Moreover, intact RB1 and wild-type p53 expression were observed. Relevantly, KRT20, KRT5/6, chromogranin A, p40, p63, HMB45, NF, TTF1, TDT (DNTT), PAX5, p16, KIT, as well as high-risk HPV and EBER1/2 (both by ISH), were negative. This report illustrates that a detailed immunohistochemical study, including STAB2 and MCPyV markers, as well as a careful clinical workup, are essential to adequately classify high-grade neuroendocrine carcinomas, especially KRT20-negative MCC.

Changes in Lysine Methylation Contribute to the Cytotoxicity of Curcumin in Colon Cancer Cells.

Epigenetic abnormalities play a critical role in colon carcinogenesis, making them a promising target for therapeutic interventions. In this study, we demonstrated that curcumin reduces colon cancer cell survival and that a decrease in lysine methylation was involved in such an effect. This correlated with the downregulation of methyltransferases EZH2, MLL1, and G9a, in both wild-type p53 (wtp53) HCT116 cells and mutant p53 (mutp53) SW480 cells, as well as SET7/9 specifically in wtp53 HCT116 cells. The effects induced by curcumin were more pronounced in wtp53 cells, where it induced a stronger apoptosis and ferroptosis. Interestingly, curcumin also reduced mutp53 expression, suggesting that it could enhance the efficacy of other therapies, particularly in overcoming drug resistance mechanisms associated with mutp53. For instance, in this study, we show that curcumin sensitized SW480 cells to SET7/9 inhibition by sinefungin, further supporting its potential as a combinatorial therapeutic agent. However, although to a lesser extent, curcumin also impaired cell survival in HCT 116 p53 null cells, suggesting that other molecular pathways or factors, beyond p53, may be involved in curcumin-induced cytotoxicity.

High GRWD1 expression may predict clinically aggressive lower grade glioma, skin cutaneous melanoma, and kidney renal clear cell carcinoma carrying wild-type p53: a systematic study based on TCGA data analysis.

Glutamate-rich WD40 repeat containing 1 (GRWD1) is a novel oncogene/oncoprotein that downregulates the p53 tumor suppressor protein through several mechanisms. One important mechanism involves binding of GRWD1 to RPL11, which competitively inhibits the RPL11-MDM2 interaction and releases RPL11-mediated suppression of MDM2 ubiquitin ligase activity toward p53. Here, we mined the TCGA (The Cancer Genome Atlas) database to gain in-depth insight into the clinical relevance of GRWD1. We found that high expression of GRWD1 is associated with a poor prognosis for lower grade glioma (LGG) of the brain, skin cutaneous melanoma (SKCM), and kidney renal clear cell carcinoma (KIRC) carrying wild-type p53. Further investigations revealed that copy number alterations in the GRWD1 gene are one determinant of GRWD1 expression level. By contrast, even in patients with a diploid GRWD1 gene, high GRWD1 expression was associated with a poor prognosis for LGG, SKCM, and KIRC carrying wild-type p53. Additional studies suggest that some transcriptional factors may be involved in regulation of GRWD1 in cancers with a diploid GRWD1 gene. Taken together, the data presented herein suggest that high expression of GRWD1 may contribute to malignant behavior, and predict a clinically unfavorable prognosis for LGG, SKCM, and KIRC carrying wild-type p53.

INOS-Produced Nitric Oxide from Cancer Cells as an Intermediate of Stemness Regulation by PARP-1 in Colorectal Cancer.

PARP-1 has been linked to the progression of several types of cancer. We have recently reported that PARP-1 influences tumor progression in CRC through the regulation of CSCs in a p53-dependent manner. In this study, we propose that nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) could act as a mediator. We evaluated the expression of iNOS in a cohort of patients previously used to analyze the effects of PARP-1 on CRC in relation to p53 status. We also developed an in vitro model in which PARP-1 was stably overexpressed. In CRC patients, iNOS expression correlated with the differentiation grade, and with a high expression of CSC markers, although only in wild-type p53 tumors, as previously found for PARP-1. In vitro, overexpression of PARP-1 induced increased growth and stemness in wild-type p53 cells, while exerting the opposite effect on mutated ones, as expected. Treatment with 1400 W, a selective inhibitor of iNOS, or gene silencing of the gene counteracted the effects of PARP-1 in both p53 wild-type and p53 mutated cells. Given that the development of resistance has been demonstrated after treatment with PARP-1 inhibitors, iNOS could be considered a new therapeutic target in CRC, although only in patients with wild-type p53 tumors.

Orphan nuclear receptor NR2E3 is a new molecular vulnerability in solid tumors by activating p53

The orphan nuclear receptor NR2E3 has emerged as a potential tumor suppressor, yet its precise mechanisms in tumorigenesis require further investigation. Here, we demonstrate that the full-length protein isoform of NR2E3 instead of its short isoform activates wild-type p53 and is capable of rescuing certain p53 mutations in various cancer cell lines. Importantly, we observe a higher frequency of NR2E3 mutations in three solid tumors compared to the reference population, highlighting its potential significance in tumorigenesis. Specifically, we identify a cancer-associated NR2E3R97H mutation, which not only fails to activate p53 but also impedes NR2E3WT-mediated p53 acetylation. Moreover, we show that the small-molecule agonist of NR2E3, 11a, penetrates tumor mass of uterine cancer patients and increases p53 activation. Additionally, both NR2E3 and 11a exhibit similar multifaceted anti-cancer properties, underscoring NR2E3 as a novel molecular vulnerability in cancer cells. We further explore drug repurposing screens of FDA-approved anti-cancer drugs to develop NR2E3-targeted combinatorial treatments, such as the 11a-Romidepsin combination in HeLa cells. The underlying molecular mechanisms of these drug synergies include the activation of p53 pathway and inhibition of oncogenic pathway like MYC. Overall, our findings suggest that NR2E3 holds promise as a therapeutic target for cancer treatment, offering new avenues for effective anti-cancer strategies.

Small molecules that targeting p53 Y220C protein: mechanisms, structures, and clinical advances in anti-tumor therapy.

The p53 protein is regarded as the "Guardian of the Genome," but its mutation is tumor progression and present in more than half of malignant tumors. The pro-metastatic property of mutant p53 makes a strong argument for targeting mutant p53 with new therapeutic strategies. However, mutant p53 was considered as a challenging target for drug discovery due to the lack of small molecular binding pockets. Among them, mutant p53 Y220C creates a narrow crevice since the side chains dynamics on protein surface, which is suitable for designing small molecules to occupy the cavity and recovery the tumor suppressing function. Here, we describe the mechanism of p53 related signal pathway and how p53 Y220C regulate the tumorigenesis. We review the two types of p53 Y220C modulators including restoring the conformation of mutant p53 Y220C protein to wild-type p53 protein and recruiting histone acetyltransferase p300/CBP to acetylate p53 Y220C thus enables p53 Y220C dependent upregulation of apoptotic genes and downregulation of DNA damage response pathways. We also report clinical advances and challenges of these molecules in p53 Y220C medicated tumor therapy.

Verruciform Acanthotic Vulvar Intraepithelial Neoplasia Harbors Recurrent Genomic Alterations Found in HPV-independent Squamous Cell Carcinoma.

The term verruciform acanthotic vulvar intraepithelial neoplasia (vaVIN) was coined to describe HPV-independent p53-wildtype lesions with characteristic clinicopathologic characteristics and association with vulvar squamous cell carcinoma (vSCC). We aimed to expand on the molecular landscape of vaVIN using comprehensive sequencing and copy number variation profiling. vaVIN diagnosis in institutional cases was confirmed by a second review, plus negative p16 and wildtype p53 by immunohistochemistry. Multigene next-generation sequencing and shallow-whole genome sequencing were used to survey for single-nucleotide variants (SNV), copy number alterations, and structural variants. Targeted TERT promoter sequencing was also carried out. Nineteen patients with vaVIN were included; 4 had concurrent vSCC. The median patient age was 74 (range 56-90) years. Genomic aberrations were noted in 18 cases (95%) as follows: PIK3CA in 10 (53%), CDKN2A in 7 (37%), HRAS in 6 (32%), FAT1 and NOTCH1-2 in 5 each (26%), TSC2 in 2 (11%), and PTEN, ARID2, and KRAS in 1 (5%) each. TERT promoter variants were detected in 11 of 13 cases successfully tested (85%). Five vaVINs harbored a TP53 variant but showed wild-type p53 immunohistochemical expression. In one of these, the concurrent carcinoma showed abnormal p53 and biallelic TP53 mutations. Out of 15 patients with follow-up (mean: 20, range: 2-50mo), vaVIN persistence/recurrence was seen in 8 (53%), and subsequent vSCC in 2 (13%). At the last encounter, 3 (20%) patients had persistent disease and 1 (7%) died of vSCC. vaVIN is characterized by a wider molecular spectrum, beyond known alterations in PIK3CA, HRAS, and ARID2, to include TERT promoter, CDKN2A, FAT1, and NOTCH1-2, which are characteristic of HPV-independent vSCC. vaVIN can occur with concurrent or subsequent carcinoma, sometimes with fatal outcomes. These findings support the concept of vaVIN as a neoplastic process within the family of HPV-independent vulvar neoplasia.

Theophylline alleviates cyclophosphamide-induced T cell senescence by downregulating acetylation of p53 at lysine 373.

Cyclophosphamide is a widely used immunosuppressive and chemotherapeutic agent in clinics. Previous studies have indicated that cyclophosphamide treatment induces cellular senescence in patients, although the underlying mechanisms remain elusive. Here, we reported that cyclophosphamide induced T cell senescence in the spleen of mice. Meanwhile, phosphoramide mustard cyclohexanamine (PM), an active metabolite of cyclophosphamide, triggered human T cell senescence. RNA sequencing analysis revealed that PM promoted senescence of primary human T cells through the activation of the p53 signaling pathway. Moreover, PM strongly increased the acetylation of p53 lysine 373 in T cells. Compared with the wild-type p53, mutating lysine 373 of p53 to arginine markedly reduced the p21 and p16 expression in PM treated Jurkat cells. Notably, we found that theophylline, an activator of histone deacetylase HDAC, ameliorated the senescence phenotype of both primary human T cells induced by PM and splenic T cells induced by cyclophosphamide in mice. Together, the results from current study could provide a potential strategy against cyclophosphamide-induced T cell senescence by inhibiting p53 acetylation.

S100A4 contributes to colorectal carcinoma aggressive behavior and to chemoradiotherapy resistance in locally advanced rectal carcinoma

To investigate the functional role of S100A4 in advanced colorectal carcinoma (Ad-CRC) and locally advanced rectal carcinoma (LAd-RC) receiving neoadjuvant chemoradiotherapy (NCRT). We analyzed histopathological and immunohistochemical sections from 150 patients with Ad-CRC and 177 LAd-RC patients treated with NCRT. S100A4 knockout (KO) HCT116 cells were also used. S100A4 expression was absent in normal mucosa but increased progressively from colorectal adenoma to carcinoma, suggesting that S100A4 regulation is an early event in colorectal carcinogenesis. In Ad-CRC, high S100A4 expression correlated with high tumor budding and nuclear β-catenin, deep invasion, lymph-vascular involvement, and unfavorable prognosis. In NCRT-treated LAd-RC, high S100A4 expression was associated with poor treatment response and short progression-free survival. S100A4 KO decreased the proliferation of HCT116 cells through activation of the p53/p21waf1 axis, and sensitized cells to adriamycin-induced apoptosis. Levels of the apoptotic marker, cleaved poly (ADP-ribose) polymerase 1, were significantly higher in samples with low S100A4 and wild type p53. Finally, we observed a direct interaction between S100A4 and p53. In conclusion, S100A4 expression engenders aggressive behavior in Ad-CRC through association with β-catenin-driven tumor buddings. S100A4 exerts anti-apoptotic and proliferative effects via inhibition of p53 in LAd-RC patients receiving NCRT, which leads to chemoradioresistance and poor prognosis.

Prognostic factors and survival outcomes of immunohistochemically detection based-molecular subtypes of endometrial cancer–analysis of 576 clinical cases

ObjectiveThe study aimed to identify distinct molecular subtypes of endometrial cancer (EC) by immunohistochemistry and to analyze their pathological characteristics, independent prognostic factors, and patient survival outcomes for potential clinical applications.Method576 patients with preoperative EC confined to the uterus were divided into three subgroups based on the immunohistochemical detection method: MMR-deficiency (MMRd), P53 wild type (P53wt) and P53 abnormal (P53abn). These subgroups were retrospectively analyzed, and their pathological characteristics, prognostic factors and survival outcomes were compared.ResultsWe identified 401 (69.6%), 123 (21.4%), and 52 (9%) cases of P53wt, MMRd, and P53abn subgroups, respectively. A significant difference was observed in the median age of onset, tumor stage, high-grade tumor differentiation, non-endometrioid carcinoma, myometrial invasion, lymphovascular invasion, the incidence of lymph node metastasis postoperative, and expression of ER and PR receptors among the three groups. Pathological type, lymphovascular invasion, ER and PR expression were identified as independent prognostic factors for disease-free survival (DFS). Additionally, pathological type, lymphovascular invasion, myometrial invasion, and PR expression were recognized as independent prognostic factors for overall survival (OS) in the study cohort. However, the survival outcome for P53abn was the worst, with lymphovascular invasion identified as an independent prognostic factor for DFS. Lymph node status, FIGO stage, and ER expression were identified as independent prognostic factors for OS.ConclusionThe study concludes that immunohistochemical detection-based subtyping of EC holds clinical practicality and can be employed to explore both pathological and clinical prognoses for EC patients.

Molecular Subtypes of Vulvar Squamous Cell Carcinoma: The Significance of HPV-Independent/p53 Wild Type.

Vulvar carcinoma is a rare disease, meeting the criteria for a "rare cancer", but its incidence is increasing, especially in women <60 years of age. Squamous cell carcinoma (VSCC) accounts for the overwhelming majority of vulvar carcinomas and is the focus of this review. As with many cancers, the increased understanding of molecular events during tumorigenesis has led to the emergence of the molecular subclassification of VSCC, which is subclassified into tumors that arise secondary to high-risk human papillomavirus infection (HPV-associated, or HPVa) and those that arise independently of HPV (HPVi), most commonly in the setting of a chronic inflammatory condition of the vulvar skin. This latter group of HPVi VSCC arises in most cases secondary to mutations in TP53, but recently, attention has focused on the uncommon TP53 wild-type HPVi VSCC. These three molecular subtypes of VSCC (HPVa, HPVi p53 abnormal, and HPVi p53 wild type), as well as their precursor lesions, cannot be diagnosed based on a routine histopathological examination or immunostaining for p53 and p16 as surrogate markers for TP53 mutation and high-risk HPV infection, respectively, are required. The molecular subtyping of VSCC shows high reproducibility and provides important prognostic information. HPVa VSCC has the most favorable prognosis, while HPVi VSCC with TP53 mutations (p53abn) has the worst prognosis, and HPVi VSCC with wild-type TP53 (p53wt) has an intermediate prognosis. In this review, we discuss the evidence supporting this molecular subclassification and its implications for the diagnosis and treatment of VSCC and its precursors.

Anticancer effects of aloe-emodin from Rheum undulatum L. through activation of the p53 pathway in human prostate cancer cells

Aloe-emodin, an anthraquinone compound naturally derived from Rheum undulatum L., has gained extensive research attention owing to its various pharmacological effects, including its potential as an anticancer, antivirus, anti-inflammatory, antibacterial, and anti-parasitic agent. It has demonstrated notable inhibitory effects against various types of cancer and cancer cells. Prostate cancer is among the most commonly identified cancers globally and remains a leading cause of cancer-associated deaths in men, often presenting challenges in early detection due to its asymptomatic nature during initial stages. The aim of present study was to determine the biological activity of aloe-emodin obtained from Rheum undulatum L. involving activation of the p53-dependent pathway in certain human prostate cancer cell lines. We explored the mechanisms underlying the anticancer effects of aloe-emodin using LNCaP cells, which include p53-wild type and phosphatase and tensin homolog-deficient mutated genes, a widely studied model in genomic research. Aloe-emodin induced apoptosis in LNCaP cells through several mechanisms, including upregulation of the cleavage of caspase-8 (a cross-linked promoter of cell death signals), phosphorylation of p53 at serine 15, DNA fragmentation, cleavage of poly [ADP-ribose] polymerase, and promotion of cell death. These findings strongly indicated that aloe-emodin's anticancer properties in human prostate cancer involve the activation of p53-induced cellular senescence. Conclusively, the findings of this study imply that aloe-emodin extracted from Rheum undulatum L. is a potential therapeutic compound for adjuvant chemotherapy that induces apoptosis and pyroptosis, an innate immune response, in preventing the progression of precancerous lesions in patients with prostate cancer.