Profiling Activins and Follistatin in Colorectal Cancer According to Clinical Stage, Tumour Sidedness and Smad4 Status

Refaat, Bassem; Zekri, Jamal; Aslam, Akhmed; Ahmad, Jawwad; Baghdadi, Mohammed; Meliti, Abdelrazak; Idris, Shakir; Sultan, Sufian; Alardati, Hosam; Saimeh, Haitham; Alsaegh, Aiman; Alhadrami, Mai; Hamid, Tahira; Naeem, Mohammed E.; Elsamany, Shereef

doi:10.3389/pore.2021.1610032

Cited by 10 publications

(14 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The sections were studied on a Leica DMi8 microscope and images were acquired from 10 random fields/section with a 20× objective. The IHC Image Analysis Toolbox in ImageJ software (https://imagej.nih.gov/ij/) was used to measure the protein expression, as described elsewhere (38,39).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Enhanced anti-cancer effects of oestrogen and progesterone co-therapy against colorectal cancer in males

et al. 2022

Self Cite

View full text Add to dashboard Cite

Although ovarian sex steroids could have protective roles against colorectal cancer (CRC) in women, little is currently known about their potential anti-tumorigenic effects in men. Hence, this study measured the therapeutic effects of 17β-oestradiol (E2) and/or progesterone (P4) against azoxymethane-induced CRC in male mice that were divided into (n = 10 mice/group): negative (NC) and positive (PC) controls, E2 (580 µg/Kg/day; five times/week) and P4 (2.9 mg/Kg/day; five times/week) monotherapies, and concurrent (EP) and sequential (E/P) co-therapy groups. Both hormones were injected intraperitoneally to the designated groups for four consecutive weeks. Similar treatment protocols with E2 (10 nM) and/or P4 (20 nM) were also used in the SW480 and SW620 human male CRC cell lines. The PC group showed abundant colonic tumours alongside increased colonic tissue testosterone levels and androgen (AR) and oestrogen (ERα) receptors, whereas E2 and P4 levels with ERβ and progesterone receptor (PGR) decreased significantly compared with the NC group. E2 and P4 monotherapies equally increased ERβ/PGR with p21/Cytochrome-C/Caspase-3, reduced testosterone levels, inhibited ERα/AR and CCND1/survivin and promoted apoptosis relative to the PC group. Both co-therapy protocols also revealed better anti-cancer effects with enhanced modulation of colonic sex steroid hormones and their receptors, with E/P the most prominent protocol. In vitro, E/P regimen showed the highest increases in the numbers of SW480 (2.1-fold) and SW620 (3.5-fold) cells in Sub-G1 phase of cell cycle. The E/P co-therapy also disclosed the lowest percentages of viable SW480 cells (2.8-fold), whilst both co-therapy protocols equally showed the greatest SW620 apoptotic cell numbers (5.2-fold) relative to untreated cells. Moreover, both co-therapy regimens revealed maximal inhibitions of cell cycle inducers, cell survival markers, and AR/ERα alongside the highest expression of cell cycle suppressors, pro-apoptotic molecules, and ERβ/PGR in both cell lines. In conclusion, CRC was associated with abnormal levels of colonic sex steroid hormones alongside aberrant protein expression of their receptors. While the anti-cancer effects of E2 and P4 monotherapies were equal, their combination protocols showed boosted tumoricidal actions against CRC in males, possibly by promoting ERβ and PGR-mediated androgen deprivation together with inhibition of ERα-regulated oncogenic pathways.

show abstract

Section: Immunohistochemistrymentioning

confidence: 99%

Enhanced anti-cancer effects of oestrogen and progesterone co-therapy against colorectal cancer in males

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…Many authors have reported that the levels of SMAD4 expression play important roles in many kinds of cancers. [22–24] The roles of SMAD4 in animal models, where SMAD4 is involved in tumor formation and the development of metastasis in prostate, colorectal and pancreatic cancers, have been confirmed. [25] In lung cancer, SMAD4 activates TGF-β signaling and contributes to tumor metastasis by regulating the TGF-β pathway.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathological and prognostic significance of SMAD4 in non-small cell lung cancer: A meta-analysis and database validation

Li¹,

Huang²,

Zhou³

et al. 2023

Medicine

View full text Add to dashboard Cite

Background: The relationship between SMAD family member 4 (SMAD4) and the clinicopathological and prognostic significance of non-small cell lung cancer (NSCLC) patients is unclear. Our aim was to investigate the association between SMAD4 expression and clinicopathological parameters and NSCLC prognosis. Methods: We searched articles in databases from inception to July 2022 to retrieve literature related to SMAD4 expression and the clinicopathological and/or prognostic significance of NSCLC patients. Odds ratios (ORs), hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. We evaluated the expression of SMAD4 and overall survival (OS) in NSCLC using the Kaplan–Meier plotter database. Results: Eight articles with 1461 NSCLC patients were included. SMAD4 expression was related to tumor differentiation (OR = 0.359, 95% CI: 0.238–0.543, P = .000), lymph node metastasis (OR = 0.469, 95% CI: 0.04–0.725, P = .001), tumor node metastasis stage (OR = 0.238, 95% CI: 0.156–0.362, P = .000) and good OS (HR = 0.592, 95% CI: 0.332–0.853, P = .000) in NSCLC. There was no significant association between SMAD4 expression and age (OR = 0.822, 95% CI: 0.515–1.312, P = .411) or sex (OR = 1.056, 95% CI: 0.675–1.653, P = .811). Furthermore, SMAD4 expression was lower in NSCLC, and a good prognosis in NSCLC (HR = 0.6, 95% CI = 0.51–0.72, P = 4.2 e-9) was shown to correlate with higher SMAD4 expression using the Kaplan–Meier Plotter database. Conclusion: SMAD4 expression is lower in NSCLC and correlated with lymph node metastasis, tumor differentiation, tumor node metastasis stage and good OS for NSCLC patients.

show abstract

“…The final diagnosis with the histopathological staging were based on institutional clinical management guidelines that followed the 8 th edition of the American Joint Committee on Cancer tumor-node-metastasis (TNM) staging system. By retrieving the pathology and surgical reports, tumors located from the cecum to the margin of hepatic flexure were categorized as right-sided cancer (RSC), whilst neoplasms located from the splenic flexure to the rectum were considered left-sided cancer (LSC) ( 4 ). All the retrieved tissue blocks were examined by consultant histopathologists in KAMC to ensure adequacy.…”

Section: Methodsmentioning

confidence: 99%

“…The ImageJ software ( https://imagej.nih.gov/ij/ ) was used to measure the protein expression by the IHC Image Analysis Toolbox, as reported elsewhere ( 4 , 41 ). Briefly, the stained areas (ROI) were identified, and the stain intensity with the percentage of stained areas were measured.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Profiling estrogen, progesterone, and androgen receptors in colorectal cancer in relation to gender, menopausal status, clinical stage, and tumour sidedness

et al. 2023

Self Cite

View full text Add to dashboard Cite

BackgroundAlthough estrogen (ERα/ERβ), progesterone (PGR), and androgen (AR) receptors are pathologically altered in colorectal cancer (CRC), their simultaneous expression within the same cohort of patients was not previously measured.MethodsERα/ERβ/PGR/AR proteins were measured in archived paired normal and malignant colon specimens (n =120 patients) by immunohistochemistry, and results were analyzed by gender, age (≤50 vs. ≥60 years), clinical stages (early-stage I/II vs. late-stage III/IV), and anatomical location (right; RSCs vs. left; LSCs). Effects of 17β-estradiol (E2), progesterone (P4), and testosterone alone or combined with the specific blockers of ERα (MPP dihydrochloride), ERβ (PHTPP), PGR (mifepristone), and AR (bicalutamide) on cell cycle and apoptosis were also measured in the SW480 male and HT29 female CRC cell lines. ResultsERα and AR proteins increased, whilst ERβ and PGR declined markedly in malignant specimens. Moreover, male neoplastic tissues showed highest AR expression, whilst ERβ and PGR weakest alongside ERα strongest expression was seen in cancerous tissues from women aged ≥60 years. Late-stage neoplasms also revealed maximal alterations in the expression of sex steroid receptors. By tumor location, LSCs disclosed significant elevations in ERα with marked declines in PGR compared with RSCs, and ERα strongest alongside PGR weakest expression was detected in advanced LSCs from women aged ≥60 years. Late-stage LSCs from females aged ≥60 years also showed weakest ERβ and strongest AR expression. In contrast, male RSC and LSC tissues exhibited equal ERβ and AR expression in all clinical stages. ERα and AR proteins also correlated positively, whereas ERβ and PGR inversely, with tumor characteristics. Concomitantly, E2 and P4 monotherapies triggered cell cycle arrest and apoptosis in the SW480 and HT29 cells, and while pre-treatment with ERα-blocker enhanced the effects of E2, ERβ-blocker and PGR-blocker suppressed the E2 and P4 anti-cancer actions, respectively. In contrast, treatment with the AR-blocker induced apoptosis, whilst co-treatment with testosterone hindered the effects. ConclusionsThis study advocates that protein expression of sex steroid receptors in malignant tissues could represent prognostic markers, as well as hormonal therapy could provide an alternative strategy against CRC, and their efficacies could be dependent on gender, clinical stage, and tumor location.

show abstract

Profiling Activins and Follistatin in Colorectal Cancer According to Clinical Stage, Tumour Sidedness and Smad4 Status

Cited by 10 publications

References 53 publications

Enhanced anti-cancer effects of oestrogen and progesterone co-therapy against colorectal cancer in males

Enhanced anti-cancer effects of oestrogen and progesterone co-therapy against colorectal cancer in males

Clinicopathological and prognostic significance of SMAD4 in non-small cell lung cancer: A meta-analysis and database validation

Profiling estrogen, progesterone, and androgen receptors in colorectal cancer in relation to gender, menopausal status, clinical stage, and tumour sidedness

Contact Info

Product

Resources

About