To evaluate the role of 17β-oestradiol (E2) in the sex-dependent progression of colorectal cancer (CRC), the present study focused on E2 signalling mediated via the nuclear receptors [oestrogen receptor (ESR)1 and ESR2] and the membrane G protein-coupled oestrogen receptor 1 (Gper1) in males and females diagnosed with CRC. This study also investigated Gper1 signalling in the CRC cell lines DLD1 and LoVo, which differ in the p53 pathway. In cancer tissue, Gper1 becomes by far the most abundant E2 receptor due to an increase in Gper1 and a decrease in ESR2 expression. These changes are more prominent in males than in females. More pronounced differences in Gper1 expression between cancer and adjacent tissues were observed in males in lower stages compared with those in higher stages of disease and females. High expression of Gper1 was associated with worse survival in males without nodal involvement but not in females. The expression of E2 receptors in the CRC cell lines DLD1 and LoVo resembles that of human cancer tissue. Silencing of Gper1 (siGper1) caused an increase in the rate of metabolism in LoVo cells with wild-type tp53. In DLD1 cells with the mutated form of tp53, siGper1 did not exert this effect. High levels of Gper1 were associated with worse survival and could contribute to sex-dependent changes in the CRC prognosis. Tumour suppressor effects of Gper1 were, at least to some extent, dependent on signalling downstream of p53, which was more frequently deficient in males than in females. Overall, this suggests that up-regulation of Gper1 (or administration of a Gper1 agonist) would be more beneficial for patients with wild-type tp53.

Colorectal cancer (CRC) is a major global health issue, with rising incidence and mortality rates. Dietary factors, especially whole grains consumption, are critical in determining CRC risk. Understanding CRC deaths and disability-adjusted life years (DALYs) related to low whole grains diets is important for prevention. The purpose of the study is to investigate temporal and geographic trends in CRC deaths and DALYs attributable to diet low in whole grains at the global, regional, and national levels from 1990 to 2021.

The data on CRC burden attributable to diet low in whole grains from 1990 to 2021 were extracted from the Global Burden of Diseases (GBD) 2021 database. We described the CRC burden attributable to diet low in whole grains across various years, genders, age groups (5-year age groups from 25 to 94 years and 95+ years), different Socio-demographic Index (SDI) regions and countries. To illustrate the temporal trends in the burden of CRC, we calculated the estimated annual percentage change (EAPC) from 1990 to 2021.

From 1990 to 2021, the global number of CRC deaths attributable to diet low in whole grains increased from 101,813 (95% UI: 42,588 to 151,170) to 186,257 (95% UI: 76,127 to 284,803), representing a 82.94% growth. Similarly, the number of DALYs increased from 2,540,867 (95% UI: 1,050,794 to 3,754,416) to 4,327,219 (95% UI: 1,754,865 to 6,578,232), representing a 70.30% growth. However, both the age-standardized mortality rate (ASMR) and age-standardized DALY rate (ASDR) exhibited a decline, with an EAPC of -0.82 (95% CI: -0.85 to -0.78) and - 0.84 (95% CI: -0.87 to -0.81), respectively. The disease burden is heavier in high SDI and high-middle SDI regions. However, between 1990 and 2021, the only region where both ASMR and ASDR increased was low-middle SDI, while in all other regions, they showed a declining trend. In 2021, East Asia had the highest number of CRC deaths and DALYs attributable to diet low in whole grains at the regional level, followed by Western Europe and High-income North America. Additionally, the burden is greater among males and the elderly. Between 1990 and 2021, the number of CRC deaths attributable to diet low in whole grains rose by 102.13% among males and by 63.20% among females. Generally, both the global age-specific mortality rate and the DALYs rate tend to increase with age. SDI demonstrates a nonlinear "S"-shaped correlation with both ASMR and ASDR of CRC attributable to diet low in whole grains. In 2021, the EAPC in ASMR of CRC attributable to diet low in whole grains was negatively associated with SDI (R = -0.402, p < 0.001), reaching the highest EAPC at approximately SDI of 0.51 and the lowest at 0.85. Similarly, the correlation between EAPC in ASDR and SDI in 2021 exhibited a similar pattern.

Despite a decline in the ASMR and ASDR of CRC attributable to diet low in whole grains from 1990 to 2021 globally, the absolute number of cases continues to increase, with a particularly notable burden observed in High-middle and High SDI regions, as well as among males and the elderly population. It is imperative to intensify efforts in CRC prevention and health education, specifically targeting these high-risk groups to raise public awareness and consumption of whole grains. Furthermore, screening initiatives should be intensified among these demographics to address the elevated risk of CRC mortality due to insufficient whole grains consumption.

Estrogen receptor β (ERβ) is the most highly expressed subtype in the colon epithelium and mediates the protective effect of estrogen against the development of colon cancer. Indeed, the expression of this receptor is inversely related to colorectal cancer progression. Structurally estrogen-like compounds, including vitamin E components, affect cell growth by binding to ERs. In the present study, cell proliferation was measured by cell counting in a Bürker hemocytometer, and ERβ expression was measured by Real-Time qPCR and immunoenzymatic methods. The results obtained show that natural δ-tocopherol (δ-Toc) and two of its semi-synthetic derivatives, bis-δ-tocopheryl sulfide (δ-Toc)2S and bis-δ-tocopheryl disulfide (δ-Toc)2S2, play an antiproliferative role and upregulate ERβ expression, similar to 17-β-estradiol (17β-E2), in human colon adenocarcinoma HCT8 cells engineered to overexpress ERβ protein (HCT8-β8). These events are not present in HCT8-pSV2neo and in HCT8-β8 pretreated with ICI 182,780, suggesting that they are mediated by the binding of compounds to ERβ, as also boosted by an in silico assay. The antiproliferative effect is independent of the intracellular redox state and (δ-Toc)2S and (δ-Toc)2S2 reduce cell proliferation at concentrations lower than that of δ-Toc and all tested compounds are also able to upregulate ERβ expression. Taken together, the data indicate that, through the involvement of ERβ activity and expression, δ-Toc, (δ-Toc)2S, and (δ-Toc)2S2 may provide potential therapeutic support against colorectal cancer.

Familial adenomatous polyposis (FAP) is a rare disease characterized by the development of adenomatous polyps in the colon and rectum already in adolescence. If left untreated, patients develop colorectal cancer (CRC) with a 100% probability. To date, the gold standard of FAP management is surgery, which is associated with morbidity and mortality. A chemopreventive agent capable of delaying, preventing and reversing the development of CRC has been sought. Several classes of drugs have been used but to date no chemopreventive drug has been found for the management of this disease. In recent years, the importance of estrogen receptors in FAP and CRC, particularly the β subtype, has emerged. Indeed, the expression of the latter is strongly reduced in adenomatous polyps and CRC and is inversely correlated with the aggressiveness of the disease. Since phytoestrogens have a high affinity for this receptor, they have been suggested for use as chemopreventive agents in FAP and CRC. A combination of phytoestrogens and insoluble fibres has proved particularly effective. In this review, the various mechanisms of action of phytoestrogens were analyzed and the effectiveness of using phytoestrogens as an effective chemopreventive strategy was discussed.

Colorectal cancer (CRC) is one of the most common causes of cancer morbidity in both sexes but shows sex differences. First, sex-specific differences in tumor recurrence and survival rates have been reported. For example, the development of CRC is found about 1.5 times higher and 4-8 years earlier in males compared to females, suggesting the protective role of estrogen in the disease. Furthermore, female patients have a higher risk of developing right-sided (proximal) colon cancer than male patients, which is known to have more aggressive clinical character compared to left-sided (distal) colon cancer. That is, left and right CRCs show differences in carcinogenic mechanism, that the chromosomal instability pathway is more common in left colon cancer while the microsatellite instability and serrated pathways are more common in right colon cancer. It is thought that there are sex-based differences on the background of carcinogenesis of CRC. Sex differences of CRC have two aspects, sexual dimorphism (biological differences in hormones and genes) and gender differences (non-biological differences in societal attitudes and behavior). Recently, sex difference of colon adenoma pathway and sexual dimorphism in the biology of gene and protein expression, and in endocrine cellular signaling in the CRC carcinogenesis have been accumulated. In addition, behavioral patterns can lead to differences in exposure to risk factors such as drinking or smoking, diet and physical activity. Therefore, understanding sex/gender-related biological and sociocultural differences in CRC risk will help in providing strategies for screening, treatment and prevention protocols to reduce the mortality and improve the quality of life. In this review, sex/gender differences in colon adenoma pathway and various aspects such as clinicopathological, biological, molecular, and socio-cultural aspects of CRC were described.

Colon cancer (CRC) is a prevalent malignancy that exhibits distinct differences in incidence, prognosis, and treatment responses between males and females. These disparities have long been attributed to hormonal differences, particularly the influence of oestrogen signalling. This review aims to provide a comprehensive analysis of recent advances in our understanding of the molecular mechanisms underlying sex differences in colon cancer and the protective role of membrane and nuclear oestrogen signalling in CRC development, progression, and therapeutic interventions. We discuss the epidemiological and molecular evidence supporting sex differences in colon cancer, followed by an exploration of the impact of oestrogen in CRC through various genomic and nongenomic signalling pathways involving membrane and nuclear oestrogen receptors. Furthermore, we examine the interplay between oestrogen receptors and other signalling pathways, in particular the Wnt/β-catenin proliferative pathway and hypoxia in shaping biological sex differences and oestrogen protective actions in colon cancer. Lastly, we highlight the potential therapeutic implications of targeting oestrogen signalling in the management of colon cancer and propose future research directions to address the current gaps in our understanding of this complex phenomenon.

The small non-coding RNA miR-34a is a p53-regulated miRNA that acts as a tumour suppressor of colorectal cancer (CRC). Oncogenesis is also negatively influenced by deregulation of the circadian system in many types of tumours with various genetic backgrounds. As the clock gene per2 was recently recognized as one of the target genes of miR-34a, we focused on the miR-34a-mediated influence on the circadian oscillator in CRC cell lines DLD1 and LoVo, which differ in their p53 status. Previously, a sex-dependent association between the expression of per2 and that of miR-34a was demonstrated in CRC patients. Therefore, we also investigated the effect of 17β-estradiol (E2) on miR-34a oncostatic functions. miR-34a mimic caused a pronounced inhibition of per2 expression in both cell lines. Moreover, miR-34a mimic significantly inhibited bmal1 expression in LoVo and rev-erbα expression in DLD1 cells and induced clock gene expression in both cell lines. miR-34a mimic caused a pronounced decrease in sirt1 and cyclin D1 expression, which may be related to the inhibition of proliferation observed after mir-34a administration in DLD1 cells. E2 administration inhibited the migration and proliferation of DLD1 cells. E2 and miR-34a, when administered simultaneously, did not potentiate each other's effects. To conclude, miR-34a strongly influences the expression of components of the circadian oscillator without respect to p53 status and exerts its oncostatic effects via inhibition of sirt1 and cyclin D1 mRNA expression. E2 administration inhibits the growth of DLD1 cells; however, this effect seems to be independent of miR-34a-mediated action. With respect to the possible use of miR-34a in cancer treatment, clock genes can be considered as off-target genes, as changes in their expression induced by miR-34a treatment do not contribute to the oncostatic functions of miR-34a. Possible ambiguous oncogenic characteristics should be taken into consideration in future clinical studies focused on miR-34a.

The pathobiological role of estrogen is controversial in colorectal cancer. Cytosine-adenine (CA) repeat in the estrogen receptor (ER)-β gene (ESR2-CA) is a microsatellite, as well as representative of ESR2 polymorphism. Though its function is unknown, we previously showed that a shorter allele (germline) increased the risk of colon cancer in older women, whereas it decreased it in younger postmenopausal women. ESR2-CA and ER-β expressions were examined in cancerous (Ca) and non-cancerous (NonCa) tissue pairs from 114 postmenopausal women, and comparisons were made considering tissue types, age/locus, and the mismatch repair protein (MMR) status. ESR2-CA repeats <22/≥22 were designated as 'S'/'L', respectively, resulting in genotypes SS/nSS (=SL&LL). In NonCa, the rate of the SS genotype and ER-β expression level were significantly higher in right-sided cases of women ≥70 (≥70Rt) than in those in the others. A decreased ER-β expression in Ca compared with NonCa was observed in proficient-MMR, but not in deficient-MMR. In NonCa, but not in Ca, ER-β expression was significantly higher in SS than in nSS. ≥70Rt cases were characterized by NonCa with a high rate of SS genotype or high ER-β expression. The germline ESR2-CA genotype and resulting ER-β expression were considered to affect the clinical characteristics (age/locus/MMR status) of colon cancer, supporting our previous findings.

The prognosis of colorectal cancer is affected by factors such as site of origin, tumor morphology, and metastasis at diagnosis, but also age and sex seem to play a role. This study aimed to investigate within the Italian population how sex and age interact in influencing certain aspects of the disease and how they affect patient survival, particularly in the metastatic cohort. Data from four cancer registries were collected, and patients were classified by sex and age (<50, 50-69, and >69 years). Two separate analyses were conducted: one for patients having right or left colon cancer with adenocarcinoma or mucinous morphology, and one for patients having metastases at diagnosis. Women showed significant differences in right colon cases from the youngest to oldest age group (36% vs. 45% vs. 60%). Men <50 years had a significantly higher mucinous carcinoma percentage than their female counterparts (22% vs. 11%), while in the oldest age group women had the highest percentage (15% vs. 11%). The metastatic pattern differed between men and women and by age. The three-year relative survival in the <50 age group was better for women than men, but this survival advantage was reversed in the oldest group. In conclusion, sex and age are factors that influence the biological and clinical characteristics of colorectal cancer, affecting the metastatic pattern as well as patient survival.

Colorectal cancer (CRC) is the third most common cancer and has the second highest cancer-related mortality in the world. The incident rates of CRC vary country-wise; however, population studies and data from different countries show a general increase in the CRC rate in young adults, males, and females ≥65 years. CRC incidence is affected by age, sex, environmental, dietary, hormonal, and lifestyle factors. Obesity is a known disease that is spreading rapidly throughout the world. A large body of literature indicates that, among many conditions, obesity is the increasing cause of CRC. Even though obesity is one of the known factors for CRC development, limited studies are available that explain the mechanistic link between obesity, sex hormones, and CRC development. Thus, this review summarizes the literature and aims to understand sex-dependent differences in CRC, especially in the context of obesity.

5-Fluorouracil (5-FU) represents one of the major constituents of chemotherapy combination regimens in colon cancer (CRC) treatments; however, this regimen is linked with severe adverse effects and chemoresistance. Thus, developing more efficient approaches for CRC is urgently needed to overcome these problems and improve the patient survival rate. Currently, 17β-estradiol (E2) has gained greater attention in colon carcinogenesis, significantly lowering the incidence of CRC in females at reproductive age compared with age-matched males.

This study measured the effects of E2 and/or 5-FU single/dual therapies on cell cycle progression and apoptosis against human HT-29 female and SW480 male primary CRC cells versus their impact on SW620 male metastatic CRC cells.

The HT-29, SW480, and SW620 cells were treated with IC₅₀ of E2 (10 nM) and 5-FU (50 μM), alone or combined (E+F), for 48 h before cell cycle and apoptosis analyses using flow cytometry.

The data here showed that E2 monotherapy has great potential to arrest the cell cycle and induce apoptosis in all the investigated colon cancer cells, with the most remarkable effects on metastatic cells (SW620). Most importantly, the dual therapy (E+F) has exerted anti-cancer activities in female (HT-29) and male (SW480) primary CRC cells by inducing apoptosis, which was preferentially provoked in the sub-G₁ phase. However, the dual treatment showed the smallest effect in SW620 metastatic cells.

this is the first study that demonstrated that the anti-cancer actions of 17β-estradiol and 5-Fluorouracil dual therapy were superior to the monotherapies in female and male primary CRC cells; it is proposed that this treatment strategy could be promising for the early stages of CRC. At the same time, 17β-estradiol monotherapy could be a better approach for treating the metastatic forms of the disease. Nevertheless, additional investigations are still required to determine their precise therapeutic values in CRC.

Chemoattractant is critical to recruitment of osteoclast precursors and stimulates tumor bone metastasis. However, the role of chemoattractant in bone metastasis of colorectal cancer (CRC) is still unclear.

Histochemistry analysis and TRAP staining were utilized to detect the bone resorption and activation of osteoclasts (OCs) after administration of CCL7 neutralizing antibody or CCR1 siRNA. qRT-PCR analysis and ELISA assay were performed to detect the mRNA level and protein level of chemoattractant. BrdU assay and Tunel assay were used to detect the proliferation and apoptosis of osteoclast precursors (OCPs). The migration of OCPs was detected by Transwell assay. Western blots assay was performed to examine the protein levels of pathways regulating the expression of CCL7 or CCR1.

OCPs-derived CCL7 was significantly upregulated in bone marrow after bone metastasis of CRC. Blockage of CCL7 efficiently prevented bone resorption. Administration of CCL7 promoted the migration of OCPs. Lactate promoted the expression of CCL7 through JNK pathway. In addition, CCR1 was the most important receptor of CCL7.

Our study indicates the essential role of CCL7-CCR1 signaling for recruitment of OCPs in early bone metastasis of CRC. Targeting CCL7 or CCR1 could restore the bone volume, which could be a potential therapeutical target. Video Abstract.

A large number of studies have suggested an inhibitory role of estrogens against colorectal cancer (CRC), but persistent controversy exists. CRC characteristics are affected by sex, age, and tumor locus, suggesting the need for a systematic study considering these factors. The purpose of this study was to verify the difference in the pathobiological role of estrogens in CRC according to patient/tumor backgrounds.

Surgical specimens from 116 postmenopausal women (≥ 70 years/o, n = 74; < 70 years/o, n = 42) were studied. Estrogen receptor-β (ER-β), the main ER in the colorectal epithelium, was immunohistochemically examined. The concentrations of estradiol (E2) and estrone (E1) were examined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). These factors were compared according to the tissue type (cancerous or non-cancerous), patients' age, tumor backgrounds (locus, histology, pathological stage, status of mismatch repair protein = MMR), and clinical outcome.

ER-β-positivity, higher E2 concentration, deficient-MMR, and medullary/mucinous histology (Med/Muc) were closely related to right-sided tumors in women who were aged ≥ 70 years /o (R-Ca ≥ 70) and also closely related to each other. ER-β reduction compared with non-cancerous counterparts was observed only in left-sided tumors of patients < 70 years /o (L-Ca < 70), non-Med/Muc, or proficient-MMR tumors.

The present results suggest that estrogens do not suppress, but rather promote, R-Ca ≥ 70, Med/Muc, or deficient-MMR tumors, whereas estrogens suppress L-Ca < 70, non-Med/Muc, or proficient-MMR tumors, confirming the difference in pathobiological role of estrogens in postmenopausal colon cancer according to the patients' age and tumor background. This may at least partly explain the controversy regarding the association between estrogens and CRC.

Hereditary non-polyposis colon cancer is a dominantly inherited syndrome of colorectal cancer (CRC), with heightened risk for younger population. Previous studies link its susceptibility to the DNA sequence polymorphism along with Amsterdam and Bethesda criteria. However, those fail in term of applicability.

To determine a clear cut-off of MSH2 gene expression for CRC heredity grouping factor. Further, the study also aims to examine the association of risk factors to the CRC heredity.

The cross-sectional study observed 71 respondents from May 2018 to December 2019 in determining the CRC hereditary status through MSH2 mRNA expression using reverse transcription-polymerase chain reaction and the disease's risk factors. Data were analyzed through Chi-Square, Fischer exact, t-test, Mann-Whitney, and multiple logistics.

There are significant differences of MSH2 within CRC group among tissue and blood; yet, negative for significance between groups. Through the blood gene expression fifth percentile, the hereditary CRC cut-off is 11059 fc, dividing the 40 CRC respondents to 32.5% with hereditary CRC. Significant risk factors include age, family history, and staging. Nonetheless, after multivariate control, age is just a confounder. Further, the study develops a probability equation with area under the curve 82.2%.

Numerous factors have significant relations to heredity of CRC patients. However, true important factors are staging and family history, while age and others are confounders. The study also established a definite cut-off point for heredity CRC based on mRNA MSH2 expression, 11059 fc. These findings shall act as concrete foundations on further risk factors and/or genetical CRC future studies.

A higher incidence of colorectal cancer (CRC) is found in males compared to females. Young women (18-44 years) with CRC have a better survival outcome compared to men of the same age or compared to older women (over 50 years), indicating a global incidence of sexual dimorphism in CRC rates and survival. This suggests a protective role for the sex steroid hormone estrogen in CRC development. Key proliferative pathways in CRC tumorigenesis exhibit sexual dimorphism, which confer better survival in females through estrogen regulated genes and cell signaling. Estrogen regulates the activity of a class of Kv channels (KCNQ1:KCNE3), which control fundamental ion transport functions of the colon and epithelial mesenchymal transition through bi-directional interactions with the Wnt/β-catenin signalling pathway. Estrogen also modulates CRC proliferative responses in hypoxia via the novel membrane estrogen receptor GPER and HIF1A and VEGF signaling. Here we critically review recent clinical and molecular insights into sexual dimorphism of CRC biology modulated by the tumor microenvironment, estrogen, Wnt/β-catenin signalling, ion channels, and X-linked genes.

Piperine, a bioactive alkaloid, is known to have anticancer activities. Hence, in this study, the effectiveness of piperine pretreatment as a strategy for radio-sensitizing colorectal adenocarcinoma cell line (HT-29) was analyzed. For this, HT-29 cells were pretreated with piperine (12.5 and 25 µg/mL) and exposed to γ-radiation (1.25 Gy) and analyzed for various effector pathways to elucidate the possible mode of action in comparison to individual treatments. The proliferation efficiency of the cells was analyzed by trypan blue dye exclusion assay and MTT assay. The synergistic effects of the combination treatment were analyzed with compuSyn software. Downstream signaling pathways leading to apoptosis were studied using flowcytometry, immunofluorescence, and immunoblot assays. It was observed that combination treatment arrested HT-29 cells at G2/M phase nearly 2.8 folds higher than radiation treatment alone, inducing the radio-resistant cells to undergo apoptosis through mitochondria-dependent pathway. In addition, activation of caspase-3 and cleavage of poly(ADP-ribose) polymerases-1, the key molecular events in apoptotic signaling, were significantly enhanced. Activation of estrogen receptor beta (ERβ), a nuclear hormone transcription factor promoting tumor suppression represents a novel clinical advance towards management and prevention of cancers. Interestingly, the expression of ERβ was increased in the cells treated with piperine. In conclusion, piperine pretreatment enhances radio-sensitization in HT-29 cells by inducing the cells to undergo apoptosis hence, can be used as a classic candidate for colon cancer sensitization towards radiotherapy. PRACTICAL APPLICATION: Piperine induces enhanced radiosensitization of colon cancer cell line (HT-29) by interfering with the cancer cell line proliferation, DNA damage, and apoptosis.