{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T20:38:22Z","timestamp":1777495102927,"version":"3.51.4"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,11,15]],"date-time":"2021-11-15T00:00:00Z","timestamp":1636934400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["por-journal.com"],"crossmark-restriction":true},"short-container-title":["Pathol. Oncol. Res."],"abstract":"<jats:p>This study explored the roles of activins and follistatin in colorectal cancers. Paired malignant and normal colonic tissues were collected from archived paraffin-embedded (<jats:italic>n<\/jats:italic> = 90 patients) alongside fresh (<jats:italic>n<\/jats:italic> = 40 patients) specimen cohorts. Activin \u03b2-subunits, follistatin and Smad4 mRNAs and proteins were measured by real-time PCR and immunohistochemistry (IHC). Mature activin-A, -B, -AB and follistatin proteins were measured by ELISA. Cancer tissues having \u2264 the 20th percentile of the Smad4 IHC score were considered as low (L-S4) group. The Smad4-intact SW480 and Smad4-null HT29 colon cancer cell lines were treated with activins and follistatin, and cell cycle was analysed by flow cytometry. The cell cycle inducing (CCND1\/CCND3) and inhibitory (p21\/p27) proteins alongside the survival (survivin\/BCL2) and pro-apoptosis (Casp-8\/Casp-3) markers were measured by immunofluorescence. Thirty-nine patients had right-sided cancers (30%) and showed higher rates of L-S4 tumours (<jats:italic>n<\/jats:italic> = 17; 13.1%) alongside worse clinicopathological characteristics relative to left-sided cancers. The \u03b2A-subunit and activin-A increased, whilst \u03b2B-subunit and activin-AB decreased, in malignant sites and the late-stage cancers revealed the greatest abnormalities. Interestingly, follistatin declined markedly in early-stage malignant tissues, whilst increased significantly in the advanced stages. All activin molecules were comparable between the early stage right- and left-sided tumours, whereas the late-stage right-sided cancers and L-S4 tumours showed more profound deregulations. <jats:italic>In vitro<\/jats:italic>, activin-A increased the numbers of the SW480 cells in sub-G1 and G0\/G1-phases, whereas reduced the HT29 cell numbers in the sub-G1 phase with simultaneous increases in the G0\/G1 and S phases. The p21\/p27\/Casp-8\/Casp-3 proteins escalated, whilst CCND1\/CCND3\/BCL2\/survivin declined in the SW480 cells following activin-A, whereas activin-A only promoted p21 and p27 alongside reduced CCND3 in the HT29 cells. By contrast, activin-AB increased the numbers of SW480 and HT29 cells in Sub-G1 and G0\/G1-phases and promoted the anti-cancer and reduced the oncogenic proteins in both cell lines. In conclusion, activins and follistatin displayed stage-dependent dysregulations and were markedly altered during the advanced stages of right-sided and L-S4 cancers. Moreover, the activin-A actions in CRC could be Smad4-dependent, whereas activin-AB may act as a Smad4-independent tumour suppressor protein.<\/jats:p>","DOI":"10.3389\/pore.2021.1610032","type":"journal-article","created":{"date-parts":[[2021,11,17]],"date-time":"2021-11-17T11:29:42Z","timestamp":1637148582000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Profiling Activins and Follistatin in Colorectal Cancer According to Clinical Stage, Tumour Sidedness and Smad4 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