Posted: February 19th, 2022

The Function of the SIRT 3 mitochondrial deacetylase in cellular physiology

 

 

 

 

 

Incidence of hepatocellular carcinoma (HCC)

Hepatocellular carcinoma (HCC) is a type of cancer that begins in the liver. It’s not the same as “secondary” liver malignancies, which have moved from many other organs to the liver. It can sometimes be surgically removed or transplanted if discovered early. Although it cannot be treated in more complex stages, diagnosis and treatment could indeed help live longer and healthier.

HCC accounts for most primary liver tumors, with cholangiocarcinoma accounting for the most remainder (Hartke, Johnson, and Ghabril, 2017). The molecular and cellular mechanisms involved in liver function are critical. The Wnt signaling pathway promotes liver homeostasis and specific hepatic properties. Wnt ligands are secreted glycoproteins that have a function in activating the Wnt/β-catenin trail. Porcupine must glycosylate and palmitoylate Wnt ligands to make them bioactive. Palmitoylation, a hydrophobic lipid modification, hinders Wnt dissolution. This process occurs in the ER. The Wnt pathway is initiated by exosomes releasing β-catenin ligands that bind to Shrivelled receptors and LRP 5 or 6. Wnt binding to Frizzled and LRP5 causes phosphorylation of LRP5/6 and enlistment of Axin to the plasma tissue. Spondin-like proteins boost Wnt signaling by binding to LGR4 and LGR5, increasing beta catenin-dependent phosphorylation of LRP6. R-spondin ligands increase β-catenin signaling by removing the transmembrane E3 ubiquitin ligases ZNRF3 and RNF43, which ubiquitinate Frizzled and LRP6 before being proteasomal destroyed. Axin recruitment to the plasma membrane enhances β-catenin stability and cytoplasmic accumulation. Wnt is moved into the nucleus to regulate gene expression and becomes a compound with T cell lymphoid influencer factor transcript factors (Perugorria et al., 2019). 

In early growth, developed tissue homeostasis, tissue, and organ redevelopment, Wnt signaling pathways are involved in a range of functions, such as cell providence purpose, cell polarisation, cell relocation, and copying. A range of humanoid diseases, such as degenerative infections, have been related to the deregulation of Wnt signaling (Krishnamurthy and Kurzrock, 2018). Even though numerous Wnt pathway components have been identified for their physiological functions, various inquiries remain unanswered about tight control and signaling changes. As a result, there is a lack of targeted therapy for Wnt-related illnesses, despite multiple efforts to do so (Nusse and Clevers, 2017). Many cancers have very active Wnt signaling. Cell signaling is regulated by the plasma membrane to serve as a barrier between the external environment and the cytosolic compartment, ensuring spatial isolation. Molecular signs from outside moving inside a cell are tightly controlled and linked to downstream signaling processes by various cell surface receptors and controllers convoluted in cell signaling (Jung and Park, 2020). There are specific membrane domains where Wnt-ligand receptor complexes attach, composed of an array of different saturated fats, steroids, and fat-anchored proteins. This is where Wnt signaling begins, and the plasma membrane plays a key role (Sezgin et al., 2017).

For typical cellular processes like growth, development, survival, regeneration, and self-renewal, the Wnt pathway is essential. Genetic and epigenetic changes disturb the Wnt/β-catenin signaling path, associated with a wide range of infections, such as various malignancies, such as colonic carcinoma and HCC. Wnt/β-catenin signaling has been disturbed in approximately one-third of all HCCs, highlighting the importance of this pathway in hepatocarcinogenesis. Both the canonical (Wnt-dependent) and the non-canonical (Wnt-independent) branches of the β-catenin pathway are critical for early growth and adult soft tissue regeneration (Oksuz et al., 2015).

In addition to growth, differentiation, and migration, Wnt signaling affects a range of physiological activities during development and homeostasis. Developing effective therapeutic approaches necessitates a thorough knowledge of pathway regulation, which has been linked to a number of disorders, including cancer. The plasma membrane components of β-catenin pathways, including ligands, (co-)receptors, and extracellular or cell-bound regulators, are changed in malignancies linked to aberrant Wnt signaling. Misregulation of the β-catenin-receptor compound and its modulators appears to be connected to metastasis and cancer progression in various malignancies. Additionally, plasma membrane composition and organization can be abused to change into different anticancer medicines that specifically target the Wnt-receptor complex, resulting in an improved treatment outcome (Ansari et al., 2017).

Cell differentiation pathways like Wnt/β-catenin and growth factor receptors (like VEGFR, as well as the receptors’ cytoplasmic intermediates (such PI3K-AKT-mTOR), are commonly altered in HCC. Somatic mutations, chromosomal abnormalities, and epigenetic modifications all play a role in HCC pathway dysregulation. As a potential biomarker for HCC treatment response, deviant trail initiation has been studied too. Away from the well-known molecular pathways, the tumor micro-milieu, non-coding RNA, and gut microorganisms have all been affected by HCC, which has opened up new therapeutic avenues (Rebouissou and Nault, 2020).

Clinicians have no clue about the causatives of all occurrences of HCC. However, they have discovered some of the factors raising the chances of developing it. Cirrhosis, binge consumption, stoutness and diabetes, anabolic steroids, iron stowing disorder, hepatitis B or C, and aflatoxin are all examples of this. When HCC is in its early stages, the symptoms are difficult to notice.

As cancer progresses, some of its symptoms likely to experience are: feeling aching in the upper abdomen, bulge or solidity in the upper abdomen, inflating or puffiness in the abdomen, lack of desire for, mass forfeiture, faintness, nausea, yellowish eyes, and skin, paleness, pallid bowel activities, and dark urination. Physical testing, including blood tests, imaging scans, and a liver biopsy, are used to detect hepatocellular cancer. As long as it’s detected early enough, it’s treatable with locoregional treatments like radiation therapy, chemotherapy, alcohol injection, targeted therapy, immunotherapy, radiofrequency ablation, surgical removal of parts of the liver, as well as liver transplantation.

Mostly, patients receive the HCC diagnosis at a progressive phase when the tumor is not resected; these treatments are ineffective. TKIs (tyrosine kinase inhibitors) constitute the only realistic choice in such circumstances, despite the fact that they treat just 30% of patients, provide only a modest increase in overall survival (three months), and cause drug resistance within six months. A method that works for everyone is impractical when it comes to HCC, as it is with many other types of cancer due to its extreme heterogeneity. A variety of therapeutic options are available based on the stage of the disease as well as the underlying condition, such as liver transplantation (Heimbach et al., 2018).

In conclusion, the underlying biological mechanisms that cause similar disease manifestations in different individuals may lead to different therapy outcomes. Medication could kill cancer for some patients. Others may have cancer that does not go away permanently or reappears. If this is the situation, you will need to seek therapy on a frequent basis to keep it under control for as long as feasible.

 

 

 

 

 

 

 

 

 

 

 

References

Ansari, A., Rahman, M.S., Saha, S.K., Saikot, F.K., Deep, A. and Kim, K.H., 2017. Function of the SIRT 3 mitochondrial deacetylase in cellular physiology, cancer, and neurodegenerative disease. Aging cell, 16(1), pp.4-16.

Hartke, J., Johnson, M. and Ghabril, M., 2017, March. The diagnosis and treatment of hepatocellular carcinoma. In Seminars in diagnostic pathology (Vol. 34, No. 2, pp. 153-159). WB Saunders.

Heimbach, J.K., Kulik, L.M., Finn, R.S., Sirlin, C.B., Abecassis, M.M., Roberts, L.R., Zhu, A.X., Murad, M.H. and Marrero, J.A., 2018. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology, 67(1), pp.358-380.

Jung, Y.S. and Park, J.I., 2020. Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex. Experimental & Molecular Medicine, 52(2), pp.183-191.

Krishnamurthy, N. and Kurzrock, R., 2018. Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors. Cancer treatment reviews, 62, pp.50-60.

Nusse, R. and Clevers, H., 2017. Wnt/β-catenin signaling, disease, and emerging therapeutic modalities. Cell, 169(6), pp.985-999.

Oksuz, Z., Serin, M.S., Kaplan, E., Dogen, A., Tezcan, S., Aslan, G., Emekdas, G., Sezgin, O., Altintas, E. and Tiftik, E.N., 2015. Serum microRNAs, miR-30c-5p, miR-223-3p, miR-302c-3p, and miR-17-5p, could be used as novel non-invasive biomarkers for HCV-positive cirrhosis and hepatocellular carcinoma. Molecular biology reports, 42(3), pp.713-720.

Perugorria, M.J., Olaizola, P., Labiano, I., Esparza-Baquer, A., Marzioni, M., Marin, J.J., Bujanda, L. and Banales, J.M., 2019. Wnt–β-catenin signaling in liver development, health, and disease. Nature Reviews Gastroenterology & Hepatology, 16(2), pp.121-136.

Rebouissou, S. and Nault, J.C., 2020. Advances in molecular classification and precision oncology in hepatocellular carcinoma. Journal of hepatology, 72(2), pp.215-229.

Sezgin, E., Levental, I., Mayor, S. and Eggeling, C., 2017. The mystery of membrane organization: composition, regulation, and roles of lipid rafts. Nature reviews Molecular cell biology, 18(6), pp.361-374.

 

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